Compositions with modulating agents

ABSTRACT

The present invention relates to a waterless composition and foam as a vehicle in which an active pharmaceutical or cosmetic agent, when added is stable or stabilized by or its destabilization is impeded by the presence of a modulating agent. The pharmaceutical or cosmetic composition and foam, includes: a waterless solvent, a modulating agent and one or more active pharmaceutical or cosmetic agents. The present invention also relates to a method of treatment administering the waterless composition and foam.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119(e) of U.S.Provisional Application Ser. No. 60/861,620, filed on Nov. 29, 2007,which is hereby incorporated by reference.

This application is a continuation-in-part application of co-pendingU.S. patent application Ser. No. 10/835,505, filed on Apr. 28, 2004,which claims the benefit of priority under 35 U.S.C. §119(e) to U.S.Patent Application Ser. No. 60/530,015, filed on Dec. 16, 2003, and U.S.Patent Application Ser. No. 60/492,385, filed on Aug. 4, 2003, allhereby incorporated in their entirety by reference.

This application is a continuation in part of U.S. patent applicationSer. No. 11/430,599, filed on May 9, 2006, which claims the benefitunder 35 U.S.C. §119(e) of U.S. Provisional Patent Application No.60/784,793, filed on Mar. 21, 2006, and of U.S. Provisional PatentApplication No. 60/679,020, filed on May 9, 2005, which are hereinincorporated by reference in its entirety.

BACKGROUND

This invention relates to pharmaceutical and cosmetic compositions,particularly waterless compositions.

External topical administration is an important route for theadministration of drugs in disease treatment. Many groups of drugs,including, for example, antibiotic, anti-fungal, anti-inflammatory,anesthetic, analgesic, anti-allergic, corticosteroid, anti-psoriasis,retinoid, vitamins and anti-proliferative medications are preferablyadministered in hydrophobic media, namely ointment. However, ointmentsoften form an impermeable barrier, so that metabolic products andexcreta from the wounds to which they are applied are not easily removedor drained away. Furthermore, it is difficult for the active drugdissolved in the carrier to pass through the white petrolatum barrierlayer into the wound tissue, so the efficacy of the drug is reduced. Inaddition, ointments and creams often do not create an environment forpromoting respiration of the wound tissue and it is not favorable to thenormal respiration of the skin. An additional disadvantage of petroleumjelly-based products relates to the greasy feeling left following theirtopical application onto the skin, mucosal membranes and wounds. Afurther problem of non aqueous compositions is achieving formulations inwhich the active agent is stable.

Some active agents are known to be generally unstable or susceptible toisomerisation or to breakdown, resulting in loss of activity and the useof stabilizers, anti oxidants antimicrobials and buffers and the like inaqueous compositions to protect active or cosmetic agents is known. Theproblems of protecting active pharmaceutical and cosmetic agents inwaterless environments, such as polar compositions are multifold and canvary according to the type of waterless environment and the nature ofthe agent being used. It has been surprisingly found that factors likesmall levels of acid residues in the raw materials can be significant ininfluencing agent stability. Similarly, the presence of low levels ofmetal ions can act to catalyze reactions or breakdown. Likewise, thepresence of agents in a waterless environment that results in ionizationor leads to oxidation can act to cause reactions or breakdown. There istherefore a need for simple and elegant solutions to stabilize activeingredients in a waterless or substantially environment.

It would be particularly advantageous and there is an unmet need to havea waterless vehicle addative that is suitable for use not merely onetype of API but is adaptable for use with one or more API's from a widerange of different types of API's with relatively minimal or minoradjustment.

Foams and, in particular, foam emulsions are complicated systems whichdo not form under all circumstances. Changes in foam emulsioncomposition, such as by the addition of active ingredients maydestabilize the foam. There is, therefore, a need for a foamcomposition, which provides desirable properties to the skin and canremain stable whilst accommodating a variety of active ingredients.

Formulations based on oil or ointment, emollients have a number ofuseful attributes making them suitable candidates for topicalpharmaceutical and cosmetic compositions including foamablecompositions. They are inherently stable and inert which are clearlydesirable characteristics. They are able to moisturize and soften theskin and in appropriate amounts can act as a protective or barrier layerand can form a barrier to water. By appropriate formulation they can actto improve drug delivery to the skin and yet remain resistant to beingwashed off. On the other hand they are by their nature greasy materialsand can be difficult to formulate particularly into a topical foamablecomposition that can deliver substantially uniform and stablecomposition or foam that ameliorates or overcomes the look and feel of agreasy material, especially where that composition is waterless orsubstantially so. It is further a problem to incorporate into such avehicle pharmaceutically effective amounts of one or more activepharmaceutical ingredients such that they are uniformly presentthroughout the formulation and are effectively delivered without the useof an alcohol in the formulation.

On one level it is far from simple or obvious to produce waterlessfoamable compositions that when released produce foams of qualitysuitable for pharmaceutical or cosmetic application. On a further levelhaving realized a carrier that will produce a waterless foam of qualitythere is an additional difficulty to be overcome, namely how to adaptthe formula and achieve a formulation, which can accept a range ofvarious active pharmaceutical and cosmetic agents such that thecomposition and active agent are stable and the foam produced remains ofquality. Specifically, one of the challenges in preparing such waterlessor substantially waterless foamable compositions is ensuring that theactive pharmaceutical or therapeutic agent does not react, isomerizes orotherwise break down to any significant extent during is storage anduse. Particularly, there remains an unmet need for improved, easy touse, stable and non-irritating foam formulations, with uniquetherapeutic or beneficial properties containing a stable or stabilizedactive pharmaceutical or cosmetic agent.

There remains an unmet need for improved, easy to use, stable andnon-irritating topical foam formulations containing a stable orstabilized active pharmaceutical or cosmetic agent having a therapeuticor beneficial effect, intended for treatment of dermal and mucosaltissues.

SUMMARY

The present invention relates to a waterless composition as a vehicle inwhich an active pharmaceutical or cosmetic agent, when added is stableor stabilized.

The present invention also relates to a foamable waterless compositionas a vehicle in which an active pharmaceutical or cosmetic agent, whenadded is stable or stabilized by the presence of a modulating agent.

The present invention more particularly relates to modulating agentsthat are able to be effective in relatively low concentrations and whichhave little or no significant effect on the compositions and on the foamcompositions of the present invention.

According to one or more embodiments there is provided a waterlesscomposition as a vehicle in which a modulating agent is incorporated andwhich is capable of stabilizing an active pharmaceutical or cosmeticagent, when added.

According to one or more embodiments there is provided a waterlessvehicle, an active agent that is susceptible, to one or more ofreaction, breakdown, ionization or oxidation and a modulating agent. Inan embodiment the waterless vehicle comprises a hydrophobic solvent. Inanother embodiment it comprises a hydrophilic solvent.

According to one or more embodiments, the carrier, includes: a waterlesssolvent, a stabilizing surfactant, and or a polymeric agent, and inwhich is incorporated a modulating agent.

According to one or more embodiments, the carrier is a foamable carrier,and includes: a waterless solvent, a stabilizing surfactant, and or apolymeric agent, and a propellant and in which is incorporated amodulating agent.

In an embodiment the carrier and modulating agent formulation is capableof stabilizing an active pharmaceutical or cosmetic agent in asubstantially waterless environment.

According to one or more embodiments there is provided a waterlesscomposition comprising one or more active agents and a carrier fortopical delivery of the one or more active agents suitable forstabilizing at least one of said one or more active agents, said carriercomprising a waterless solvent and an effective amount of a modulatingagent;

-   -   wherein the at least one active agent is chemically unstable in        the carrier in the absence of a modulating agent;    -   wherein the modulating agent is capable of and is selected to        modulate or adjust the artificial pH of the carrier to an        artificial pH or to provide an artificial pH buffering effect        such that the chemical stability of the at least one active        agent is increased as compared to its stability in the carrier        without the modulating agent.

According to one or more embodiments of the present invention,pharmaceutical or cosmetic composition is foamable and, includes: awaterless solvent, a stabilizing surfactant, and or a polymeric agent, amodulating agent, a propellant and one or more active pharmaceutical orcosmetic agents.

According to one or more embodiments of the present invention, theactive agent itself can have characteristics of a modifying agent.

According to one or more embodiments of the present invention, thecarrier, includes:

-   -   a. a waterless solvent comprising about 25% to about 98% of at        least polar solvent selected from the group consisting of (1) a        polyol; and (2) a polyethylene glycol or combinations thereof;    -   b. a modulating agent;    -   c. a stabilizing agent selected from the group consisting of a        surface-active agent; and about 0.01% to about 5% by weight of        at least one polymeric agent or mixtures thereof; wherein the        carrier is shakable and wherein if the composition is stored in        an aerosol container and comprises a liquefied or compressed gas        propellant at a concentration of about 3% to about 25% by weight        of the total composition it will upon release expand to form a        breakable foam.

According to one or more embodiments the active agent is susceptible toreaction, breakdown, ionization, or oxidization.

According to one or more embodiments of the present invention, thefoamable pharmaceutical composition, includes:

-   -   1. a waterless solvent comprising about 25% to about 98% of at        least polar solvent selected from the group consisting of (1) a        polyol; and (2) a polyethylene glycol or combinations thereof;    -   2. a modulating agent;    -   3. a stabilizing agent selected from the group consisting of a        surface-active agent and about 0.01% to about 5% by weight of at        least one polymeric agent;    -   4. a liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition; and    -   5. an effective amount of an active pharmaceutical or cosmetic        agent;        wherein the carrier is shakable and wherein the composition is        stored in an aerosol container and upon release expands to form        a breakable foam.

According to one or more embodiments there is provided a foamablewaterless composition comprising:

-   -   a. a therapeutically effective concentration of one or more        active agents;    -   b. a carrier for topical delivery of the one or more active        agents suitable for stabilizing at least one of said one or more        active agents, comprising        -   i. about 25% to about 98% of at least polar solvent selected            from the group consisting of (1) a polyol; and (2) a            polyethylene glycol;        -   ii. 0% to about 75% of a secondary polar solvent;        -   iii. an effective amount of a modulating agent iv. a            stabilizing agent selected from the group consisting of a            surface-active agent; about 0.01% to about 5% by weight of            at least one polymeric agent and mixtures thereof.        -   v. a liquefied or compressed gas propellant at a            concentration of about 3% to about 25% by weight of the            total composition    -   wherein the at least one active agent is chemically unstable in        the carrier in the absence of a modulating agent;    -   wherein the modulating agent is capable of and is selected to        modulate or adjust the artificial pH of the carrier to an        artificial pH or to provide an artificial pH buffering effect        such that the chemical stability of the at least one active        agent is increased as compared to its stability in the carrier        without the modulating agent.    -   wherein the carrier is shakable or flowable; and    -   wherein the composition is stored in an aerosol container and        upon release expands to form a breakable foam.

The present invention further relates to said composition comprising oneor more additional active agents.

The present invention further relates to said composition comprising oneor more additional or secondary polar solvents.

In some embodiments, the foamable cosmetic or pharmaceutical compositionis non-flammable, wherein said gas propellant containshydrofluorocarbon.

According to one or more embodiments there is provided a method oftreating a disorder of mammalian subject, comprising:

-   -   administering a composition to a target site, the composition        comprising:    -   one or more active agents and a carrier for topical delivery of        the one or more active agents suitable for stabilizing at least        one of said one or more active agents, said carrier comprising a        waterless solvent and an effective amount of a modulating agent;    -   wherein the at least one active agent is chemically unstable in        the carrier in the absence of a modulating agent;    -   wherein the modulating agent is capable of and is selected to        modulate or adjust the artificial pH of the carrier to an        artificial pH or to provide an artificial pH buffering effect        such that the chemical stability of the at least one active        agent is increased as compared to its stability in the carrier        without the modulating agent.

According to one or more embodiments there is also provided a method oftreating a disorder of mammalian subject, comprising:

-   -   administering a foamable composition to a target site, the        composition comprising:        -   a foamable waterless composition comprising:            -   a. a therapeutically effective concentration of one or                more active agents;            -   b. a carrier for topical delivery of the one or more                active agents suitable for stabilizing at least one of                said one or more active agents, comprising                -   i. about 25% to about 98% of at least polar solvent                    selected from the group consisting of (1) a polyol;                    and (2) a polyethylene glycol;                -   ii. 0% to about 75% of a secondary polar solvent;                -   iii. an effective amount of a modulating agent                -   iv. a stabilizing agent selected from the group                    consisting of a surface-active agent; about 0.01% to                    about 5% by weight of at least one polymeric agent                    and mixtures thereof.                -   v. a liquefied or compressed gas propellant at a                    concentration of about 3% to about 25% by weight of                    the total composition    -   wherein the at least one active agent is chemically unstable in        the carrier in the absence of a modulating agent;    -   wherein the modulating agent is capable of and is selected to        modulate or adjust the artificial pH of the carrier to an        artificial pH or to provide an artificial pH buffering effect        such that the chemical stability of the at least one active        agent is increased as compared to its stability in the carrier        without the modulating agent.    -   wherein the carrier is shakable or flowable; and    -   wherein the composition is stored in an aerosol container and        upon release expands to form a breakable foam.

According to one or more embodiments there is also provided foamablewaterless composition comprising:

-   -   a. a therapeutically effective concentration of one or more        active agents;    -   b. a carrier delivery of the one or more active agents suitable        for stabilizing at least one of said one or more active agents,        comprising        -   i. about 25% to about 98% of at least polar solvent selected            from the group consisting of (1) a polyol; and (2) a            polyethylene glycol;        -   ii. 0% to about 75% of a secondary polar solvent;        -   iii. an effective amount of an modulating agent        -   iv. a stabilizing agent selected from the group consisting            of a surface-active agent; about 0.01% to about 5% by weight            of at least one polymeric agent and mixtures thereof.        -   v. a liquefied or compressed gas propellant at a            concentration of about 3% to about 25% by weight of the            total composition    -   wherein the at least one active agent is chemically unstable in        the carrier in the absence of a modulating agent; wherein the        modulating agent comprises an effective amount of one or more        agents that are capable of impeding said destabilization and or        are capable of stabilizing the active agent by chelating a metal        ion such that the modulating agent is capable of reducing in the        waterless carrier the availability of metal ions so the        stability of at least one active agent is improved when compared        to its stability in the carrier without the modulating agent;    -   wherein the carrier is shakable or flowable; and    -   wherein the composition is stored in an aerosol container and        upon release expands to form a breakable foam.

According to one or more embodiments there is also provided a carrierwhere the modulating agent acts by impeding ionization and or byimpeding oxidation.

According to one or more embodiments there is also provided a foamablewaterless carrier for use with a therapeutically effective concentrationof one or more active agents comprising:

-   -   (i) about 25% to about 98% of at least polar solvent selected        from the group consisting of (1) a polyol; and (2) a        polyethylene glycol; 0% to about 75% of a secondary polar        solvent;    -   (ii) an effective amount of a modulating agent    -   (iii) a stabilizing agent selected from the group consisting of        a surface-active agent; about 0.01% to about 5% by weight of at        least one polymeric agent and mixtures thereof.    -   (iv) a liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition    -   wherein at least one active agent if present is susceptible, to        one or more of reaction, breakdown, ionization or oxidation;    -   wherein the modulating agent comprises an effective amount of        one or more agents that are capable of impeding said        destabilization and or are capable of stabilizing the active        agent primarily by modulating or adjusting the artificial pH of        the carrier such that the modulating agent is capable of        producing in the waterless carrier an artificial pH or an        artificial pH buffering effect at about a pH or pH range in        which the stability of at least one active agent is improved        when compared to its stability in the carrier without the        modulating agent and or by chelating a metal ion such that the        modulating agent is capable of reducing in the waterless carrier        the availability of metal ions so the stability of at least one        active agent is improved when compared to its stability in the        carrier without the modulating agent;    -   wherein the carrier is shakable or flowable; and    -   wherein the composition is stored in an aerosol container and        upon release expands to form a breakable foam.

The present invention further provides a method of treating, alleviatingor preventing a disorder of mammalian subject, comprising administeringa therapeutically effective amount of the above-mentioned compositionsto an afflicted target site.

The present invention further provides use of a therapeuticallyeffective amount of the above-mentioned compositions as a medicament orin the manufacture of a medicament.

The present invention further provides a therapeutically effectiveamount of the above-mentioned compositions for use as a medicament or inthe manufacture of a medicament.

All % values are provided on a weight (w/w) basis.

DETAILED DESCRIPTION

In one or more embodiments there is provided a waterless composition foruse as a vehicle in which an active pharmaceutical or cosmetic agent,when added is stable or stabilized. Active pharmaceutical and cosmeticagents are more generally referred to as a therapeutic agent.

In one or more embodiments there is provided a waterless composition asa vehicle in which a modulating agent is incorporated and which iscapable of stabilizing an active pharmaceutical or cosmetic agent, whenadded.

In an embodiment the carrier and modulating agent formulation is capableof stabilizing an active pharmaceutical or cosmetic agent in asubstantially waterless or mon aqueous environment.

In an embodiment the carrier and modulating agent formulation is capableof stabilizing an active pharmaceutical or cosmetic agent in asubstantially waterless environment, where the active agent has low orminimal susceptibility to water and can withstand up to about 10% waterand more preferably upto about 5% water.

In one or more embodiments there is provided a waterless composition foruse as a vehicle in which an active pharmaceutical or cosmetic agent,when added is stable or stabilized by the presence of a modulatingagent.

In one or more embodiments there is provided a foamable waterlesscomposition for use as a vehicle in which an active pharmaceutical orcosmetic agent, when added is stable or stabilized by the presence of amodulating agent.

According to one or more embodiments, it is possible to make excellentlotions, creams, ointments and foams from waterless compositions. Suchcompositions containing a modulating agent as described herein are idealcarriers for active pharmaceutical ingredients that are soluble in polarsolvents and which may be potentially unstable in an aqueousenvironment, for example, following a change in pH, or the introductiona metal catalyst or in the presence of an ionization or oxidation agent.

It has been found that differences in the level and type of residues incosmetic and pharmaceutical grade materials and agents can significantlyand seriously influence the stability of an active pharmaceutical orcosmetic agent. Whilst it might be expected that active agents would bemore stable in pure raw materials with practically no residues it wassurprisingly observed that small levels of residues in raw materialswere actually helpful in improving the stability of and stabilizingactive ingredients in certain waterless compositions. On the other handactive ingredients were unstable in certain other waterlesscompositions.

In the waterless polar environments the concepts of pH, pK, and the likeare artificial and may only give approximate guidance. It has beensurprisingly found that in a non-classical waterless polar environmentof foamable carriers, compositions and foam's that active ingredientscan be susceptible to break down, isomerization, oxidisation or reactionin the presence of acid or basic residues, which in small quantities areable in a non classical way to take the active agent outside itspreferred environmental window and facilitate instability. Likewise suchbreakdown etc. could be catalyzed by the presence of metal ions in thewaterless polar environment. Following investigation it has beendiscovered that the introduction of an acid or base or buffer in a nonclassical non-aqueous polar environment of foamable carriers,compositions and foam's can act to prevent or impede such breakdown etc.Similarly, the introduction of a chelating agent can also act to preventor impede catalyzation of such breakdown etc. Likewise, introduction ofan anti ionization or antioxidation agent may also act to prevent orimpede such reaction etc.

It has been surprisingly discovered that one can modulate theenvironment of a non-aqueous foamable, carrier, composition or foam toprovide a stable environmental window for the active agent in thenon-aqueous environment. The modifying or modulating affect of themodulating agent on the waterless environment prevents or minimizes aso-called ‘change in the artificial pH range’ and/or locks up availablemetal ions which could otherwise act as a catalyst in the waterlessenvironment and/or impedes ionization or oxidation of the active agent.

Following investigation, modulating agents are identified, which bytheir presence are able to stabilize active pharmaceutical or cosmeticagents in a waterless or substantially waterless environment. Moreparticularly, they can be effective at relatively low concentrationsthat have little or no significant effect on the foam compositions ofthe present invention.

According to one or more embodiments there is provided a waterlesscomposition as a vehicle in which a modulating agent is incorporated andwhich is capable of stabilizing an active pharmaceutical or cosmeticagent, when added.

According to one or more embodiments there is provided a waterlessvehicle, an active agent that is susceptible, to one or more ofreaction, breakdown, ionization or oxidation and a modulating agent. Inan embodiment the waterless vehicle comprises a hydrophobic solvent. Inanother embodiment it comprises a hydrophilic solvent.

According to one or more embodiments, the carrier, includes: a waterlesssolvent, a stabilizing surfactant, and or a polymeric agent, and inwhich is incorporated a modulating agent.

According to one or more embodiments, the carrier is a foamable carrier,and includes: a waterless solvent, a stabilizing surfactant, and or apolymeric agent, and a propellant and in which is incorporated amodulating agent.

According to one or more preferred embodiments, the carrier comprises astabilizing agent comprising a surfactant and a polymeric agent. This isparticularly helpful for foamable compositions where the combination canbe synergistic or complimentary in providing a robust stable foam ofquality with a reasonable collase time.

In an embodiment the carrier and modulating agent formulation is capableof stabilizing an active pharmaceutical or cosmetic agent in asubstantially waterless environment.

According to one or more embodiments, pharmaceutical or cosmeticcomposition is foamable and, includes: a waterless solvent, astabilizing surfactant, and or a polymeric agent, a modulating agent, apropellant and one or more active pharmaceutical or cosmetic agents.

According to one or more embodiments, the active agent itself can havecharacteristics of a modifying agent.

According to one or more embodiments, the carrier, includes:

-   -   (a) a waterless solvent comprising about 25% to about 98% of at        least polar solvent selected from the group consisting of (1) a        polyol; and (2) a polyethylene glycol or combinations thereof;    -   (b) a modulating agent;    -   (c) a stabilizing agent selected from the group consisting of a        surface-active agent and about 0.01% to about 5% by weight of at        least one polymeric agent and mixtures thereof;        wherein the carrier is shakable or flowable and wherein if the        composition is stored in an aerosol container and further        comprises a liquefied or compressed gas propellant at a        concentration of about 3% to about 25% by weight of the total        composition it will upon release expand to form a breakable        foam.

According to one or more embodiments the active agent is susceptible toreaction, breakdown, ionization, or oxidization.

According to one or more embodiments, the active agent itself can havecharacteristics of a modifying agent.

According to one or more embodiments, the foamable carrier, includes:

-   -   1. a waterless solvent comprising about 25% to about 98% of at        least polar solvent selected from the group consisting of (1) a        polyol; and (2) a polyethylene glycol or combinations thereof;    -   2. a modulating agent;    -   3. a stabilizing agent selected from the group consisting of a        surface-active agent; and about 0.01% to about 5% by weight of        at least one polymeric agent and mixtures thereof; and    -   4. a liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition;        wherein the composition is shakable or flowable; and        wherein the composition is stored in an aerosol container and        upon release expands to form a breakable foam.

According to one or more embodiments, the foamable pharmaceuticalcomposition, includes:

-   -   1. a waterless solvent comprising about 25% to about 98% of at        least polar solvent selected from the group consisting of (1) a        polyol; and (2) a polyethylene glycol or combinations thereof;    -   2. a modulating agent;    -   3. a surface-active agent;    -   4. about 0.01% to about 5% by weight of at least one polymeric        agent;    -   5. a liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition; and    -   6. an effective amount of an active pharmaceutical or cosmetic        agent;        wherein the carrier is shakable or flowable; and        wherein the composition is stored in an aerosol container and        upon release expands to form a breakable foam.

The problem of producing a pharmaceutical composition that can provide astable or stabilized environment or he more formidable problem afoamable composition which can produce a breakable foam of quality and astabilized environment so that the active pharmaceutical agent does notsubstantially break down over a reasonable time period sufficient fornormal pharmaceutical or cosmetic use is surprisingly resolved by havingboth a polymeric agent and modulating agent present in the foamablecomposition.

In one or more embodiments the polymeric agent is selected from abioadhesive agent, a gelling agent, a film forming agent and a phasechange agent and can be from about 0.01% to about 5% by weight,preferably 0.2 to 3%.

In one or more embodiments the ratio of polymeric agent to surfactant isabout 1:10 to about 10:1; about 1:5 to about 5:1; about 3:7 to about7:3; and about 2:1 to about 1:2.

The provision and selection of polymeric agent is however notstraightforward. The polymers should be miscible or swell in thewaterless solvent. It has been found that in the case of modifiedcellulose that lower molecular weight cellulose polymer derivatives arepreferable.

In one or more preferred embodiments the polymeric agent ishydroxypropyl cellulose.

In another preferred embodiments the polymeric agent is or Carbomer suchas Carbopol 934®.

According to one or more embodiments, the pre-foamable carrier; thepre-foamable pharmaceutical or cosmetic composition; the foamablecarrier, or the foamable pharmaceutical or cosmetic composition furtherincludes 0.1% to about 75% of a secondary polar solvent.

In one or more embodiments there is provided a vehicle additive,preferably a foamable vehicle additive that is suitable for use with notmerely one type of active pharmaceutical ingredient (“API”) but isadaptable for use with one or more API's from a wide range of differenttypes of API's with appropriate and usually relatively minimal or minoradjustment. For example, by altering the amount of a component or by theaddition or replacement of a buffer, stabilizer, anti ionization agentor an antioxidant as would be appreciated by a person skilled in the artwith the benefit of the teachings herein. In one or more otherembodiments there is provided one or more pharmaceutical or cosmeticbase compositions that are suitable for use with modulating agents.

In one or more embodiments there is provided a vehicle additive,preferably a foamable one that is suitable for use as a vehicle base fordelivery for API's, which are by their nature unstable or reactive orisomerizes or oxidize.

In a further embodiment the modulating agent is preferably between about0.05% to about 5% by weight of the composition.

In a further embodiment the surfactant and polymeric agent and theiramounts are selected so that the composition is sufficiently shakable orin certain limited cases so that it is flowable albeit not shakable sothat extrusion and substantially uniform composition formation,particularly foam extrusion and formation is not hampered. To thisextent, the maximum effective amount of surfactant and polymeric agentthat may be used may be limited by the need for shakability and as aminimum by the need for flowability.

In a further embodiment of the present invention the propellant ispreferably between about 5% to about 12% by weight of the composition.

In one or more embodiments of the pharmaceutical or cosmetic foamableproduct is non-flammable.

By waterless is meant that the composition contains no or substantiallyno, free or unassociated or absorbed water. It will be understood by aperson of the art that the waterless solvents and substances misciblewith them of the present invention can be hydrophilic and can containwater in an associated or unfree or absorbed form and may absorb waterfrom the atmosphere and the ability to do so is its hygroscopic watercapacity.

In one or more embodiments the carrier comprises an activepharmaceutical or cosmetic agent, which degrades in the presence ofwater, and in such cases the present of water in the composition isclearly not desirable. Thus, in certain preferred embodiments, thecomposition is waterless. In other embodiments the active agent maytolerate the presence of a small amount of water and the waterlesscomposition is substantially non-aqueous. The term “substantiallynon-aqueous” is intended to indicate that the waterless composition haswater content below about 5%, preferably below about 2%, such as belowabout 1.5%.

In one or more embodiments the active agent has low or minimalsensitivity and can tolerate water to about 10% or less.

Upon release from an aerosol container, the foamable carrier forms anexpanded foam suitable for the treatment of an infected surface and fortopical administration to the skin, a body surface, a body cavity or amucosal surface.

Waterless Solvent

In one or more embodiments of the present invention the waterlesssolvent comprises about 25% to about 98% of at least a polar solventselected from the group consisting of (1) a polyol; and (2) apolyethylene glycol or combinations thereof.

In one or more embodiments of the present invention the waterlesssolvent comprises about 0.1% to about 75% of a secondary polar solvent.

Polar Solvent

The identification of a “polar solvent”, as used herein, is not intendedto characterize the solubilization capabilities of the solvent for anyspecific active agent or any other component of the foamablecomposition. Rather, such information is provided to aid in theidentification of materials suitable for use as a part in the foamablecompositions described herein.

Polyol

In an embodiment of the present invention, the polar solvent is apolyol. A polyol is an organic substance that contains at least twohydroxy groups in its molecular structure.

In one or more embodiments, the foamable carrier contains at least onediol (a compound that contains two hydroxy groups in its molecularstructure). Examples of diols include propylene glycol (e.g.,1,2-propylene glycol and 1,3-propylene glycol), butanediol (e.g.,1,2-butanediol, 1,3-butanediol, 2,3-butanediol and 1,4-butanediol),butanediol (e.g., 1,3-butanediol and 1,4-butenediol), butynediol,pentanediol (e.g., pentane-1,2-diol, pentane-1,3-diol, pentane-1,4-diol,pentane-1,5-diol, pentane-2,3-diol and pentane-2,4-diol), hexanediol(e.g., hexane-1,6-diol hexane-2,3-diol and hexane-2,56-diol), octanediol(e.g., 1,8-octanediol), neopentyl glycol, 2-methyl-1,3-propanediol,diethylene glycol, triethylene glycol, tetraethylene glycol, dipropyleneglycol and dibutylene glycol.

In one or more embodiments, the foamable carrier contains at least onetriol (a compound that contains three hydroxy groups in its molecularstructure), such as glycerin, butane-1,2,3-triol, butane-1,2,4-triol andhexane-1,2,6-triol.

In one or more embodiments, the polyol is a mixture of polyols. In oneor more embodiments, the mixture of polyols contains at least one dioland at least one triol. According to certain embodiments the ratiobetween the diol and triol is between 9:1 and 1:1.

In one or more embodiments, part of mixture of polyols is a saccharide.Exemplary saccharides include, but are not limited to monosaccharide,disaccharides, oligosaccharides and sugar alcohols.

A monosaccharide is a simple sugar that cannot be hydrolyzed to smallerunits. Empirical formula is (CH₂O)n and range in size from trioses (n=3)to heptoses (n=7). Exemplary monosaccharide compounds are ribose,glucose, fructose and galactose.

Disaccharides are made up of two monosaccharides joined together, suchas sucrose, maltose and lactose.

A sugar alcohol (also known as a polyol, polyhydric alcohol, orpolyalcohol) is a hydrogenated form of saccharide, whose carbonyl group(aldehyde or ketone, reducing sugar) has been reduced to a primary orsecondary hydroxyl group. They are commonly used for replacing sucrosein foodstuffs, often in combination with high intensity artificialsweeteners to counter the low sweetness. Some exemplary sugar alcohols,which are suitable for use according to the present invention aremannitol, sorbitol, xylitol, maltitol, lactitol. (Maltitol and lactitolare not completely hydrogenated compounds—they are a monosaccharidecombined with a polyhydric alcohol). Mixtures of polyols, including (1)at least one polyol selected from a diol and a triol; and (2) asaccharide are contemplated within the scope of the present invention.

Polyethylene Glycol

In an embodiment of the present invention, the polar solvent consists ofa polymerized ethylene glycol, namely polyethylene glycol, which is alsotermed “PEG”. Exemplary PEGs are provided in the following table.

Av. Molecular Composition weight Appearance Melting point (° C.) PEG 200190~210 Oily liquid PEG 300 285~315 Oily liquid PEG 400 380~420 Oilyliquid PEG 600 570~630 Oily liquid 17~22 PEG 1000  950~1050 Solid 35~40PEG 4000 3800~4400 Solid 53~58 PEG 6000 5600~6400 Solid 55~60 PEG 80007500~8500 Solid 58~65

Thus, in an embodiment of the present invention, the PEG is selectedfrom the group consisting of PEG 200, PEG 300, PEG 400, PEG 600, PEG1000, PEG 4000, PEG 6000 and PEG 8000. The foamable carrier according tothe present invention can contain a single PEG or a mixture of two ormore PEGs. PEGs having molecular weight of more that about 1000 possessgelling properties; i.e., they increase the viscosity of a composition.Therefore, by combining PEGs with different molecular weights/meltingpoints, one can attain varying levels of flowability as desirable forthe treatment of a given target site. The concentration of the PEGshould be in a level that results in viscosity, prior to filling of thecomposition into aerosol canisters, of less than 12,000 CPs, and morepreferably, less than 10,000 CPs.

Secondary Polar Solvent

Optionally, a secondary polar solvent is added to the foamablecomposition of the present invention. The secondary polar solvent isselected from a variety of organic solvents that are typically miscibleon both water and oil. Examples of polar solvent that can be containedin the foamable carrier of the present invention include dimethylisosorbide, tetrahydrofurfuryl alcohol polyethyleneglycol ether(glycofurol), DMSO, pyrrolidones, (such as N-Methyl-2-pyrrolidone and1-Methyl-2-pyrrolidinone), ethyl proxitol, dimethylacetamide (DMAc),PEG-type surfactants and alpha hydroxy acids, such as lactic acid andglycolic acid.

Appropriate use of a secondary solvent in a waterless foam compositioncan help improve delivery of active agents to a target area. Foamcompositions of the present invention, for which the solvent includes asecondary solvent, can increase the levels of the active agent in thewaterless composition and thus, provide high delivery and improvedtherapy.

Solubilization and Penetration Enhancement

In many cases, polyols, PEGs and polar solvents possess a highsolubilizing power and thus, they can enable increased concentrations ofa pharmaceutical active agent. Polyols, PEGs and polar solvents are alsoknown for their skin penetration enhancement properties. Theseproperties enable high drug bioavailability in the target area oftreatment, resulting in an enhanced therapeutic effect. Occasionally,combinations of a polyol, PEGs and a secondary polar solvent, exhibit anincreased permeability across the skin, as suggested, for example, inEur J Pharm Biopharm. 1998 November; 46(3):265-71.

Thus, in one or more embodiments, the foamable carrier contains (1) atleast one polar solvent, selected from a polyol (selected from a dioland a triol) and PEG; and (2) at least one secondary polar solvent.

In one or more embodiments, the foamable carrier contains (1) a mixtureof at least two polyols; and (2) at least one secondary polar solvent.In additional embodiments, the foamable carrier contains a mixture of atleast one polyol and at least one PEG; yet in other embodiments thefoamable carrier contains (1) a mixture of at least one polyol and atleast one PEG and (2) at least one secondary polar solvent.

According to certain embodiments the ratio between the polyol and/or PEGand the secondary polar solvent is between 9:1 and 1:1.

In certain embodiments, the polyol is selected from the group consistingof propylene glycol, hexylene glycol and glycerin (and mixturesthereof); and the secondary polar solvent is selected from the groupconsisting of dimethyl isosorbide, diethylene glycol monoethyl ether, aliquid polyethylene glycol and glycofurol.

In certain embodiments, the foamable carrier contains (1) at least onepolyol; and (2) dimethyl isosorbide.

Short chain alcohols, such as ethanol and propanol are known as polarsolvents, however, according to one or more embodiments, the compositionof the present invention is substantially alcohol-free, i.e., free ofshort chain alcohols. Short chain alcohols, having up to 5 carbon atomsin their carbon chain skeleton and one hydroxyl group, such as ethanol,propanol, isopropanol, butanol, iso-butanol, t-butanol and pentanol, areconsidered less desirable polar solvents due to their skin-irritatingeffect.

Thus, in certain embodiments, the composition is substantiallyalcohol-free and includes less than about 5% final concentration oflower alcohols, preferably less than about 2%, more preferably less thanabout 1%. However, in other embodiments, a short chain alcohol can beincluded in the composition, as long as the ratio between the shortchain alcohol and the polyol is less than 1:4 by weight.

Modulating Agent

The term modulating agent is used to describe an agent which can improvethe stability of or stabilize a carrier or a foamable composition and oran active agent by modulating the effect of a substance or residuepresent in the carrier or composition. The substance or residue may forexample be acidic or basic and potentially alter an artificial pH in awaterless or substantially non aqueous environment or it may be one ormore metal ions which may act as a potential catalyst in a waterless orsubstantially non aqueous environment or it may be an ionisation agentor it may be an oxidizing agent.

In one or more other embodiments the modulating agent is used in awaterless composition. In one or more embodiments the modulating agentis used in a substantially non aqueous composition

In one or more embodiments the modulating agent is used to describe anagent which can affect pH in an aqueous solution.

The agent can be any of the known buffering systems used inpharmaceutical or cosmetic formulations as would be appreciated by a manof the art. It can also be an organic acid, a carboxylic acid, a fattyacid an amino acid, an aromatic acid, an alpha or beta hydroxyl acid anorganic base or a nitrogen containing compound.

In one or more further embodiments the modulating agent is used todescribe an agent, which is a chelating or sequestering or complexingagent that is sufficiently soluble or functional in the waterlesssolvent to enable it to “mop up” or “lock” metal ions.

In the embodiment modulating agent is used to describe an agent whichcan effect pH in an aqueous solution the term modulating agent moreparticularly means an acid or base or buffer system or combinationsthereof, which is introduced into or is present in and acts to modulatethe ionic or polar characteristics and any acidity or basesity balanceof a waterless or substantially non aqueous carrier, composition,foamable carrier or foamable composition or resultant foam of thepresent invention.

The substance or residue can be introduced into the formulation from anyone or more of the ingredients, some of which themselves may have acidicor basic properties. For example the polymer or solvent may containbasic residues in which case it may be desirable or beneficial to add anacid. Alternatively the surfactant may contain some acid residues inwhich case the addition of a base may be desirable and beneficial. Insome cases more than one ingredient may contain residues which mayameliorate or compound their significance. For example if one ingredientprovided weak acid residues and another stronger acid residues theartificial pH in a waterless environment should be lower. In contrast,if one residue was acid and the other basic the net effect in theformulation maybe significantly reduced. In some circumstances theactive ingredient may favor an acidic pH or more significantly may needto be maintained at a certain acidic pH otherwise it may readilyisomerize, chemically react or breakdown, in which case introducingacidic components might be of help. Likewise in some circumstances theactive ingredient may favor a basic pH or more significantly may need tobe maintained at a certain basic pH otherwise it may readily hydrolyse,undergo rearrangement, isomerize, chemically react or breakdown, inwhich case introducing basic components might be of help. In anembodiment of the present invention sufficient modulating agent is addedto achieve an artificial pH in which the active agent is preferablystable. Such artificial pH may be acidic, maybe basic or may be neutral.

The terms pH, pKa, and pKb, buffers and the like are used in classicalmeasurements of an aqueous solution. Such measurements are artificial ina waterless environment. Nevertheless, reference to and descriptionbelow of such terms are made for convenience and clarity, since suchterms are well defined and understood with reference to aqueoussolutions and further due to the lack of an appropriate uniform way ofdescribing and identifying the artificial or virtual pH, pK etc in awaterless environment in relation to the present invention. Althoughpredictions of artificial pH can be made using dilution techniques ofmeasurements of waterless formulations diluted in water they areformulation sensitive and specific and have to be carefully calibratedwith complex formulas.

Waterless medium can be polar and protic yet it does not conform toclassical ionic behavior.

A buffer, as defined by Van Slyke [Van Slyke, J. Biol. Chem. 52, 525(1922)], is “a substance which by its presence in solution increases theamount of acid or alkali that must be added to cause unit change in pH”.

A buffer solution is a solution of a definite pH made up in such a waythat this pH alters only gradually with the addition of alkali or acid.Such a solution consists of a solution of a salt of the week acid in thepresence of the three acid itself. The pH of the solution is determinedby the dissociation equilibrium of the free acid.

An acid can be a strong acid or a weak acid. A strong acid is an acid,which is a virtually 100% ionized in solution. In contrast, a week acidis one which does not ionize fully when it is dissolved in water. Thelower the value for pKa, the stronger is the acid and likewise, thehigher the value for pKa the weaker is the acid.

A base can be a strong base or a weak base. A strong base is something,which is fully ionic with 100% hydroxide ions. In contrast, a weak baseis one which does not convert fully into hydroxide ions in solution. Thelower the value for pKb, the stronger is the base and likewise, thehigher the value for pKb the weaker is the base.

In general terms, three factors, which influence the strength of a base,are firstly the ease with which the lone pair takes up a hydrogen ion;secondly, the stability of ions being formed and thirdly, the way theyinteract with water such that if they pick up hydrogen ion's morereadily it is a stronger base.

An acid in an amount to affect the composition's pH selected from thegroup consisting of:

(a) An alpha hydroxyl acid of formula I:

(R_(a))(R_(b))C(OH)COOH;  I

or a pharmaceutically acceptable salt, lactone, or solvate thereof,wherein R_(a) and R_(b) are independently selected from the groupconsisting of H, F, Cl, Br, and saturated or unsaturated, isomeric ornon-isomeric, straight, branched, or cyclic C₁-C₂₅ alkyl, aralkyl, oraryl groups, wherein each of R_(a) and R_(b) may be optionallysubstituted with an OH, SH, CHO, COOH group;

(b) An aliphatic beta hydroxyacid of formula II:

(R_(a))(R_(b))C(OH)C(R_(c))(R_(d))COOH;  II

or a pharmaceutically acceptable salt, lactone, or solvate thereof,wherein R_(a), R_(b), R_(c) and R_(d) are independently selected fromthe group consisting of H, F, Cl, Br, and saturated or unsaturated,isomeric or non-isomeric, straight, branched, or cyclic C₁-C₂₅ alkyl,aralkyl, or aryl groups, wherein each of R_(a) and R_(b) may beoptionally substituted with an OH, SH, CHO, COOH group.

Exemplary alpha hydroxyl acids and beta hydroxyl acids include, but arenot limited to alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid,alpha-hydroxyisocaproic acid, alpha-hydroxyisovaleric acid, atrolacticacid, beta-hydroxybutyric acid, beta-phenyl lactic acid,beta-phenylpyruvic acid, citric acid, pyruvic acid, galacturonic acid,glucoheptonic acid, glucoheptono 1,4-lactone, gluconic acid,gluconolactone, glucuronic acid, glucuronolactone, glycolic acid, lacticacid, mandelic acid, mucic acid, pyruvic acid, saccharic acid, saccharicacid 1,4-lactone, tartaric acid and tartronic acid, 3-Hydroxybutanoicacid, quinic acid, isocitric acid, tropic acid, trethocanic acid,chlorolactic acid, citramalic acid, agaricic acid, aleuritic acid,pantoic acid, lactobionic acid, piscidic acid, hexylosonic acid or theanhydride thereof.

(c) An aromatic acid.

Exemplary aromatic acids include, but are not limited to benzoic acid,toluic acid, dimethyl benzoic acid, phthalic acid and nicotinic acid(heterocyclic).

(d) an aromatic hydroxyl acid of formula IIIa, IIIb and IIIc:

The aromatic ring can contain solely carbon atoms or a combination ofcarbon atoms and other atoms (heterocyclic), wherein R₁, R₂, R₃ and R₄are independently selected from the group consisting of H, F, Cl, Br,and saturated or unsaturated, isomeric or non-isomeric, straight,branched, or cyclic C₁-C₂₅ alkyl, aralkyl, or aryl groups.

Formula IIIa, wherein R is H, is identified as salicylic acid, yetanother example of an aromatic hydroxyl acid is acetylsalicylic acid.

(e) an alpha ketoacid of formula IV:

(R_(a))COCOO(R_(b));  IV

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein R_(a) and R_(b) are independently selected from the groupconsisting of H and saturated or unsaturated, isomeric or non-isomeric,straight, branched, or cyclic C₁-C₂₅ alkyl, aralkyl, or aryl groups,wherein R_(a) may be optionally substituted with an F, Cl, Br, I, OH,CHO, COOH, or alkoxy group having 1 to 9 carbon atoms;

(f) An aliphatic carboxylic acid.

Short chain carboxylic acids include formic acid, acetic acid andpropionic acid.

A fatty acid is a carboxylic acid often with a long unbranched aliphatictail (chain), which is either saturated or unsaturated. Carboxylic acidsas short as butyric acid (4 carbon atoms) are considered to be fattyacids, while fatty acids derived from natural fats and oils may beassumed to have at least 8 carbon atoms, as exemplified in the followinglist:

-   -   Butyric (butanoic acid): CH₃(CH₂)₂COOH    -   Caproic (hexanoic acid): CH₃(CH₂)₄COOH    -   Caprylic (octanoic acid): CH₃(CH₂)₆COOH    -   Nonanoic acid: CH₃(CH₂)₇COOH    -   Capric (decanoic acid): CH₃(CH₂)₈COOH    -   Lauric (dodecanoic acid): CH₃(CH₂)₁₀COOH    -   Myristic (tetradecanoic acid): CH₃(CH₂)₁₂COOH    -   Palmitic (hexadecanoic acid): CH₃(CH₂)₁₄COOH    -   Stearic (octadecanoic acid): CH₃(CH₂)₁₆COOH    -   Arachidic (eicosanoic acid): CH₃(CH₂)₁₈COOH    -   Behenic (docosanoic acid): CH₃(CH₂)₂₀COOH    -   Octacosanoic: CH₃(CH₂)₂₆COOH

Optionally, the carbon atom chain of the fatty acid may have at leastone double bond, as exemplifies in the following list:

-   -   Oleic acid: CH₃(CH₂)₇CH═CH(CH₂)₇COOH    -   Linoleic acid: CH₃(CH₂)₄—CH═CHCH₂CH═CH(CH₂)₇COOH    -   Alpha-linolenic acid: CH₃CH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₇COOH    -   Arachidonic acid    -   CH₃(CH₂)₄—CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₃COOH    -   Eicosapentaenoic acid    -   Docosahexaenoic acid    -   Erucic acid: CH₃(CH₂)₇CH═CH(CH₂)11COOH

Alpha-linolenic, docosahexaenoic, and eicosapentaenoic acids areexamples of omega-3 fatty acids. Linoleic acid and arachidonic acid areomega-6 fatty acids. Oleic and erucic acid are omega-9 fatty acids.

A further class of carboxylic acids according to the present inventioncomprises a carboxylic acid, wherein the carbon atom chain is branched,such as valproic acid. The carbon chain of the fatty acid or fattyalcohol can be substituted with a hydroxyl group, such as 12-hydroxystearic acid.

Short chain carboxylic acids such as formic acid and acetic acid arereasonably strong acids (pKa 3.77 and 4.76, respectively). Longer chainfatty acids have higher pKa values. Nonanoic acid, for example, has apKa of 4.96.

(g) a dicarboxylic acid

In the context of the present invention, a dicarboxylic acid is anorganic compound, having two carboxylic acid moieties on its carbon atomskeleton. They have the general molecular formula HOOC—(CH₂)_(n)—COOH.

In an embodiment of the present invention, the dicarboxylic acid is ashort-chain dicarboxylic acid. The simplest short-chain dicarboxylicacid are oxalic acid (n=0), malonic acid (n=1), succinic acid (n=2) andglutaric acid (n=3).

Additional members of dicarboxylic acid group are derived from naturalproducts or from synthesis, having “n” value from 4 up to 21. In one ormore embodiments of the present invention, the dicarboxylic acid isselected from the group consisting of adipic acid (hexanedioic acid;n=4), pimelic acid (heptanedioic acid; n=5), suberic acid (octanedioicacid; n=6), azelaic acid (nonanedioic acid; n=7), sebacic acid(decanedioic acid; n=8) and dodecanedioic acid (n=10).

In an additional embodiment, the dicarboxylic acid contains 10 to 32carbon atoms in their carbon atom skeleton, such as brassylic acid(n=11), thapsic acid (n=14), 14-methylnonacosanedioic acid (C29) and14,15-dimethyltriacontanedioic acid (C30).

The carbon atom skeleton of the dicarboxylic acid can be saturated orunsaturated, such as in the case of undecylenic acid, maleic acid andfumaric acid.

In an additional embodiment, the dicarboxylic acid is branched, i.e.,the carbon atom skeleton of the dicarboxylic acid can be substitutedwith at least one group selected from the group consisting of R, F, Cl,Br, OH, OR, SH, CHO, COOH, and NR_(a)R_(b), wherein R, R_(a) and R_(b)are independently selected from the group consisting of H, saturated orunsaturated, isomeric or non-isomeric, straight, branched, or cyclicC₁-C₂₅ alkyl, aralkyl, or aryl groups. Exemplary branched dicarboxylicacids include aspartic acid, alpha-ketoglutaric acid, adipic acid2-amino, aconitic acid, benzene dicarboxylic acid, citramalic acid,citric acid, cystathionine, glucuronic acid, glutamic acid, itaconicacid, malic acid, mucic acid, oxalacetic acid, diamino pimelic acid,saccharic acid, dimethyl succinic acid, tartaric acid, tartronic acid,

(h) Miscellaneous organic acids

In an embodiment of the present invention, the organic acid is selectedfrom the group consisting of ascorbic acid, isoascorbic acid,ethanesulfonic acid, glycerophosphoric acid, acetohydroxamic acid,aconitic acid, alpha-ketocaproic acid, aminomalonic acid, hippuric acid,hydrochloric acid, methanesulfonic acid, oxalic acid, phosphoric acid,sorbic acid, iminodiacetic acid, carnitine, nicotinic acid andretinoids, such as retinoic acid and isotretinoin.

(i) Amino acid

The a-COOH and a-NH₂ groups in amino acids are capable of ionizing (asare the acidic and basic R-groups of the amino acids). As a result oftheir ionizability the following ionic equilibrium reactions may bewritten:

R—COOH<-------->R—COO—+H+

R—NH₃+<-------->R—NH₂+H+

The equilibrium reactions, as written, demonstrate that amino acidscontain at least two weakly acidic groups. However, typically thecarboxyl group is a far stronger acid than the amino group. Atphysiological pH (around 7.4) the carboxyl group will be unprotonatedand the amino group will be protonated. An amino acid with no ionizableR-group would be electrically neutral at this pH. This species is termeda zwitterion.

Like typical organic acids, the acidic strength of the carboxyl, aminoand ionizable R-groups in amino acids can be defined by the associationconstant, Ka or more commonly the negative logarithm of Ka, the pKa. Thenet charge (the algebraic sum of all the charged groups present) of anyamino acid, peptide or protein, will depend upon the pH of thesurrounding aqueous environment. As the pH of a solution of an aminoacid or protein changes so too does the net charge. This phenomenon canbe observed during the titration of any amino acid or protein. When thenet charge of an amino acid or protein is zero the pH will be equivalentto the isoelectric point: pI.

The following table lists amino acids and their pKa's:

pK₁ pK₂ Acid (COOH) (NH₂) pK R Group Glycine 2.4 9.8 Alanine 2.4 9.9Valine 2.2 9.7 Leucine 2.3 9.7 Isoleucine 2.3 9.8 Serine 2.2 9.2 ~13Threonine 2.1 9.1 ~13 Cysteine 1.9 10.8 8.3 Methionine 2.1 9.3 AsparticAcid 2.0 9.9 3.9 Asparagine 2.1 8.8 Glutamic Acid 2.1 9.5 4.1 Glutamine2.2 9.1 Arginine 1.8 9.0 12.5 Lysine 2.2 9.2 10.8 Histidine 1.8 9.2 6.0Phenylalanine 2.2 9.2 Tyrosine 2.2 9.1 10.1 Tryptophan 2.4 9.4 Proline2.0 10.6

In addition, nonprotein amino acids are also suitable in accordance tothe present invention, including but not limited to: B-alanine(3-alanine), 4-aminobutyrate (GABA), 3-cyanoalanine (B-cyanoalanine),2-aminobutyric acid, 2-methylene-4-aminobutyric acid,3-methylene-4-aminobutyric acid, 2-aminoisobutyric acid,5-aminolevulinic acid, 2-amino-4-methylhexanoic acid (homoisoleucine),2-amino-4-methylhex-4-enoic acid, 2-amino-4-methylhex-5-ynoic acid,2-amino-3-methylpentanoic acid, 2-aminoadipic acid, 4-ethylideneglutamicacid, 3-aminoglutaric acid, 2-aminopimelic acid, N4-ethylasparagine,N4-methylasparagine, erythro-4-methylglutamic acid, 4-methyleneglutamicacid, 4-methyleneglutamine, N5-methylglutamine, N5-ethylglutamine(theanine), N5-isopropylglutamine, 2-amino-4-(aminoxy)butyric acid(canaline), 2,4-diaminobutyrate, N4-acetyl-2,4-diaminobutyrate,N4-lactyl-2,4-diaminobutyrate, N4-oxalyl-2,4-diaminobutyrate,2,3-diaminopropionic acid, N3-acetyl-2,3-diaminopropionic acid,N3-methyl-2,3-diaminopropionic acid, N3-oxalyl-2,3-diaminopropionicacid, N6-acetyllysine, N6-methyllysine, N6-trimethyllysine (laminine),ornithine (2,5-diaminopentanoic acid), saccharopine(N-6-(2′-glutamyl)lysine, 2,6-diaminopimelic acid,N4-(2-hydroxylethyl)asparagine, erythro-3-hydroxyaspartic acid,4-hydroxyarginine, 4-hydroxycitrulline, threo-4-hydroxyglutamic acid,3,4-dihydroxyglutamic acid, 3-hydroxy-4-methylglutamic acid,3-hydroxy-4-methyleneglutamic acid, 4-hydroxy-4-methylglutamic acid,4-hydroxy-glutamine, N5-(2-hydroxyethyl)glutamine, 5-hydroxynorleucine,threo-4-hydroxyhomoarginine, homoserine, O-acetylhomoserine,O-oxalylhomoserine, O-phosphohomoserine, 4-hydroxyisoleucine,5-hydroxymethylhomocysteine, threo-3-hydroxyleucine, 5-hydroxyleucine,2-hydroxylysine, 4-hydroxylysine, 5-hydroxylysine,N6-acetyl-5-hydroxylysine, N6-trimethyl-5-hydroxylysine,4-hydroxyornithine, mimosine, 4-hydroxynorvaline, 5-hydroxynorvaline,2-amino-4,5-dihydroxypentanoic acid, 2-amino-4-hydroxypimelic acid,4-hydroxyvaline, O-acetylserine, O-phosphoserine, pipecolic acid,(piperidine-2-carboxylic acid), 3-hydroxypipecolic acid,trans-4-hydroxypipecolic acid, trans-5-hydroxypipecolic acid,5-hydroxy-6-methylpipecolic acid, 4,5-dihydroxypipecolic acid,trans-3-hydroxyproline, trans-4-hydroxyproline,trans-4-hydroxymethylproline, azetidine-2-carboxylic acid,N-(3-amino-3-carboxypropyl)azetidine-2-carboxylic acid,4,5-dehydropipecolic acid (baikiain), 3-amino-3-carboxypyrrolidone(cucurbitine), 2-(cyclopent-2′-enyl)glycine, 5-hydroxytryptophan,albizziine (2-amino-3-ureidopropionic acid), arginosuccinic acid,canavinosuccinic acid, citrulline, homoarginine, homocitrulline,indospicine, O-ureidohomoserine, 6-hydroxykynurenine,3-(4-aminophenyl)alanine, 3-(3-aminomethylphenyl)alanine,3-(3-carboxyphenyl)alanine, 3-carboxytyrosine,3-(3-hydroxymethylphenyl)alanine, 3-(3-hydroxyphenyl)alanine,3-(3,4-dihydroxyphenyl)alanine (L-DOPA), 2-(phenyl)glycine,2-(3-carboxyphenyl)glycine, 2-(3-carboxy-4-hydroxyphenyl)glycine,2-(3-hydroxyphenyl)glycine, 2-(3,5-dihydroxyphenyl)glycine,4-aminopipecolic acid, guvacine,2-amino-4-(isoxazolin-5-one)-2-yl)butyric acid, lathyrine,tetrahydrolathyrine and ornithin.

In an embodiment of the present invention the organic modulating agentis a dimer or oligomer of amino acids.

In an embodiment of the present invention the organic modulating agentis an organic base.

In an embodiment the organic base is a nitrogen-containing organiccompound.

In an embodiment the nitrogen-containing organic modulating compound isselected from, primary, secondary, tertiary and quaternary amines. Theorganic primary amine may include alkylamines such as methylamine andethylamine; ethanolamine such as monoethanolamine andmonoisopropanolamines; diamines such as ethylenediamine and1,2-diaminopropane. The organic secondary amines include dialkylaminessuch as dimethylamine and diethylamine, diethanolamine anddiisopropanolamine; N-methylethanolamine and N-ethylethanolamine. Theorganic tertiary amines include trialkylamines such as triethylamine andtriethylamine; triethanolamine; N-methyldiethanolamine andtri-isopropanolamine. The quaternary compounds preferably include basiccholine.

In an embodiment the nitrogen-containing organic modulating compound isan amide. Amides are derivatives of oxoacids in which an acidic hydroxygroup has been replaced by an amino or substituted amino group.Compounds having one, two, or threeacyl groups on a given nitrogen aregenerically included and may be designated as primary, secondary andtertiary amides, respectively.

In an embodiment the nitrogen-containing organic modulating compound isan amine oxide. amine oxide are compounds derived from tertiary aminesby the attachment of one oxygen atom to the nitrogen atom: R₃N⁺—O—.

In an embodiment the nitrogen-containing organic modulating compound isa lactam. Lactams are cyclic amides amino carboxylic acids, having a1-azacycloalkan-2-one structure, or analogues having unsaturation orheteroatoms replacing one or more carbon atoms of the ring, asexemplified in the following structures:

Urea is another example of a nitrogen-containing modulating compound.

The modulating agent to the foamable composition of the presentinvention is useful for stabilizing pharmaceutical and cosmetic activeagents which are unstable in certain pH conditions. It is known, forexample, that active agents, which contain ester bond in their structuretend to undergo hydrolysis of the ester bond at basic pH levels.Therefore, the addition of an agent which avoids the formation of basicpH condition and thus, prevents degradation of such active agents. Manysteroid compounds are known to undergo rearrangement at high pH, andagain, adding an acidic modulating agent helps prevent such degradation.This is clearly exemplified by the stark difference in stability resultsfor BMV in the absence and presence of a modulating agent asdemonstrated in Examples 1 and 2 below. Another example of apH-sensitive active agent is vitamin D, which degrades at low pH levels.In such a case, the addition of a basic modulating agent, such astriethanol amine is useful to maintain acceptable stability of thisactive agents as can be seen an exemplified in Example 5 below.

In certain cases, the stability of an active agent may be influenced bysmall quantities of, for example, metal ions in the waterlesscompositions. Such metal ions may act as a catalyst in facilitating thereaction or breakdown of the agent. Thus the modulating agent can be achelating or sequestering or complexing agent on its own. In one or moreembodiments of the present invention there is provided an effectiveamount of chelating agent which is sufficiently soluble or functional inthe waterless solvent to enable it to “mop up” or “lock” metal ions.

For instance it is known that Polyphenols through the chelation oftransition-metal ions, particularly those of iron and copper inhibitfree radical formation and the propagation of free radical reactions(Brown et al. in Biochem. J. 330, 1173 1178 (1998)). Citric acid, aminoacids, and thylenediaminetetraacetic acid also form chelates withmetallic ions such as copper and iron, thus avoiding their catalyticaction on the oxidation of lipids. Most of these chelating agentsexhibit little or no antioxidant activity when used alone, and thereforethey are considered as synergistic agents of other antioxidants. Thus,they increase, to a great extent, the action of primary antioxidants.

In one or more embodiments of the present invention the chelating agentis selected from the group consisting of acetyl trihexyl citrate,aminotrimethylene phosphonic acid, beta-alanine diacetic acid, bismuthcitrate, calcium disodium edta, citric acid, cyclohexanediaminetetraacetic acid, diammonium citrate, dibutyl oxalate, diethyl oxalate,diisobutyl oxalate, diisopropyl oxalate, dilithium oxalate, dimethyloxalate, dipotassium edta, dipotassium oxalate, dipropyl oxalate,disodium edta, disodium edta-copper, disodium pyrophosphate, edta,etidronic acid, hedta, methyl cyclodextrin, oxalic acid, pentapotassium,triphosphate, pentasodium aminotrimethylene phosphonate, pentasodiumpentetate, pentasodium triphosphate, pentetic acid, phytic acid,potassium citrate, sodium citrate, sodium dihydroxyethylglycinate,sodium gluceptate, sodium gluconate, sodium hexametaphosphate, sodiummetaphosphate, sodium metasilicate, sodium oxalate, sodiumtrimetaphosphate, tea-edta, tetrahydroxypropyl ethylenediamine,tetrapotassium etidronate, tetrapotassium pyrophosphate, tetrasodiumedta, tetrasodium etidronate, tetrasodium pyrophosphate, tripotassiumedta, trisodium edta, trisodium hedta, trisodium nta, trisodiumphosphate, malic acid, fumaric acid, maltol, succimer, penicillamine,dimercaprol, and desferrioxamine mesilate.]

Other authorized chelating agents are listed pursuant to annex 1,paragraph E.3.1 of regulation (EC) No 2003 (See Directive 67/548/EEC OJ196, 16.8 1967, p1) and are also incorporated herein by reference.

In one or more preferred embodiments of the present invention thechelating agent is selected from the group consisting ofethylenediaminetetraacetic acid (“EDTA”) and salts thereof such asdisodium EDTA, tetrasodium EDTA and calsium disodium EDTA;diethylenetriaminepentaacetic acid (“DTPA”) and salts thereof;hydroxyethlethylenediaminetriacetic acid (“HEDTA”) and salts thereof andnitrilotriacetic acid (“NTA”); more preferably EDTA, HEDTA and theirsalts; most preferably EDTA and its salts.

In one or more embodiments of the present invention a preferred nonlimiting example of the chelating agent is EDTA. Typically, thechelating and sequestering agent is present in the composition at alevel of up to about 5.0%, preferably 1.0 percent, by weight, of thecomposition.

Combinations of Modulating Agents may be a useful aspect of the presentinvention. For example, as will be appreciated by a man of the artcombinations of a strong acid and a weak base; a weak acid and a strongbase: a weak acid and a strong acid; a weak base and a strong base; aweak base and a second weak base; and a weak acid and a second weakacid; may prove more effective in protecting or stabilizing an activeagent in the waterless solvents of the present invention than a base oracid on its own. It will be understood that each of the active agentsmay have an artificial pH at which it can be more stable in a waterlesscomposition. For example, ascorbic acid in aqueous solution is known tobe more stable at an acidic pH of about 5.4. It is therefore desirableto add a combination of modulating agents in a waterless compositionthat will generate an artificial pH approximately of the order of orequivalent to that at which ascorbic acid is more stable in a waterlessmedium. In order to do so it will be appreciated a man of the art thatthat some adjustment will have to be made as ascorbic acid is itself astrong acid and displays the characteristics of a modulating agent.Similarly chelating agents may be usefully used in combination withanother modulating agent such as an acid, a base or a buffer system orwith various combinations of modulating agents.

The modulating agent to the foamable composition of the presentinvention is further useful for adjusting the pH of the target area ofapplication. Skin is the first line of defense against all elements,such as microorganisms, wind, and pollutants, and it's the acid mantle,a fine film with a slightly acidic pH on the surface of the skin thatprovides protection for the skin. It plays a very important role as anintegral part of the barrier function of the stratum corneum. Recentstudies have demonstrated that increased enzyme activity ofphospholipase A2 is related to the formation of the acid mantle in thestratum corneum. This combination makes the skin less permeable to waterand other polar compounds. Normal skin surface pH is between 4 and 6.5in healthy people, though it varies among the different areas of theskin. Newborn infants do have a higher skin surface pH compared toadults, but this normalizes within three days. Therefore, it isimportant to maintain skin surface pH in order to prevent susceptibilityto bacterial skin infections or skin damage and disease. Thus, adding amodulating agent, which contributes to the stabilization of skin pH atthe desirable level, is advantageous.

In the same fashion, adding an acidic modulating agent to a foamablecomposition, which is intended for vaginal application is advantageous,since the best protection against vaginal infection is attained in pHlower than 4.

While the organic modulating agent can serve to stabilize an activeagent in the foam composition, it often provides additional therapeuticproperties to the composition. The following table exemplifies, in anon-limiting fashion, the therapeutic benefits expected from an organicmodulating agent. It is to be understood that this table provides anon-exhaustive list of modulating agents that possess therapeuticeffects, however, many other compounds listed in the presentspecification also possess therapeutic benefits.

Exemplary therapeutic Class Examples properties Alpha hydroxy acidsLactic acid Humectant Glycolic acid Keratnocyte growth modifierAnti-psoriasis Anti acne Beta hydroxyl acid Salicylic acid KeratolyticAntiinflammatory Short chain carboxylic Propionic acid Antiinfectiveacid Butyric acid Fatty acids Nonanoic acid Hair growth stimulantBehenic acid Antiinflammatory Antiinfective Humectant Skin protectionUnsaturated fatty acids Omega-3 fatty acids Radical scavenger Omega-6fatty acids Anti-oxidant Aromatic acids Benzoic acid AntiinflammatoryPhthalic acid Anti-acne Nicotinic acid Anti-pigmentation AntiinfectiveInsect repellant Dicarboxylic acids Malonic acid, succinicAntiinflammatory acid, glutaric acid, Keratolytic adipic acid, pimelicAnti-acne acid, suberic acid, Anti-rosacea azelaic acid, sebacicAnti-pigmentation acid Amino acids Keratnocyte growth modifier Hairgrowth stimulant Sebum control Retinoids Retinoic acid AntiinflammatoryIsotretinoin Keratolytic Anti-acne Anti-rosacea Anti-pigmentationNitrogen containing Urea Humectant Keratolytic Anti-psiriasis

In one or more embodiments, the modulating agent may also be apreservative or an antioxidant or an ionization agent. Any preservative,antioxidant or ionization agents suitable for pharmaceutical or cosmeticapplication may be used. Non limiting examples of antioxidants aretocopherol succinate, propyl galate, butylated hydroxy toluene and butylhydroxy anisol. Ionization agents may be positive or may be negativedepending on the environment and the active agent or composition that isto be protected. Ionization agents may for example act to protect orreduce sensitivity of active agents. Non limiting examples of positiveionization agents are benzyl conium chloride, and cetyl pyridiumchloride. Non limiting examples of negative ionization agents are sodiumlauryl sulphate, sodium lauryl lactylate and phospholipids.

In one or more embodiments the modulating agent is a flavonoid.

Flavonoids (or bioflavonoids) are a large group of polyphenolicantioxidant compounds, which often occur as glycosides and areubiquitously present in foods of plant origin. Some flavonoids (e.g.quercetin, rutin) are available as dietary supplements. Flavonoids canbe further subdivided into:

-   -   flavonols (e.g. kaempferol, quercetin and myricetin)    -   flavones (e.g. apigenin and luteolin)    -   flavonones (e.g. hesperetin, naringenin, eriodictyol)    -   flavan-3-ols (e.g. (+)-catechin, (+)-gallocatechin,        (−)-epicatechin, (−)-epigallocatechin)    -   anthocyanins (e.g. cyanidin, delphinidin, malvidin,        pelargonidin, peonidin, petunidin)    -   proanthocyanidins.

More than 4000 flavonoids have been identified, and many have beenstudied. Most are colorless but some are responsible for the brightcolors of many fruit and vegetables. Flavonoids are distinguished fromthe carotenoids.

Flavonoids appear to

-   -   act as scavengers of free radicals, including superoxide anions,        singlet oxygen, and lipid peroxyl radicals (they have        antioxidant properties);    -   sequester metal ions;    -   inhibit in vitro oxidation of LDL cholesterol;    -   inhibit cyclo-oxygenase, leading to lower platelet aggregation,        decreased thrombotic tendency and reduced anti-inflammatory        activity;    -   inhibit histamine release;    -   improve capillary function by reducing fragility of capillary        walls and thus preventing abnormal leakage; and inhibit various        stages of tumor development (animal studies only).

The activities of flavonoids are dependent on their chemicalstructure.Estimates of dietary flavonoid intake vary from 10 to 100 mgdaily, but may be several hundreds of milligrams a day. Dietarysupplements of quercetin and rutin provide around 500 mg in a singledose.

Flavonoids may have a potential role in the prevention of CVD, cancerand cataracts and possibly other diseases, for anti-viral activity, andthey may be useful in treating ulcers. include hemorrhoids, allergy,asthma, menopausal symptoms and the prevention of habitual abortion.

Quercetin

As a dietary supplement, quercetin is promoted for prevention andtreatment of atherosclerosis and hyperlipidaemia, diabetes, cataracts,hay fever, peptic ulcer, inflammation, prevention of cancer and fortreating prostatitis. A preliminary, double-blind, placebo-controlledtrial in chronic non-bacterial prostatitis showed that quercetin reducedpain and improved quality of life, but had no effect on voidingdysfunction.

Rutin

As a dietary supplement, rutin is used to reduce capillary permeabilityand treat symptoms of varicose veins. In combination with bromelain andtrypsin, rutin is used to treat osteoarthritis.

A non limiting list of flavonoid compounds is: benzquercin, diosmin,ethoxazorutoside, flavodate, sodium hesperidin, leucocianido,monoxerutin, oxerutin, quercetin, rutoside, rosmarinic acid. The aboveinformation was noted from Dietary Supplements, Electronic Version,Pharmaceutical Press 2007.

In an embodiment a single flavonoid is provided and in a furtherembodiment a combination of two or more flavonoid are provided. Incertain embodiments the flavonoids act synergistically. In an embodimentwater soluble flavonoids are combined with water insoluble flavonoids.It is known for example that whole polyphenolic extracts have greaterantioxidant effect than their known individual components. In anembodiment flavonoids are used in combination with other phenolics. Inan embodiment one or more flavonoids are provided in combination withone or more vitamins. In an embodiment flavonoids are provided that aremore reactive than the vitamins. In an embodiment the flavonoids act asa conservational agent.

Microsponges

The Microsponges are rigid, porous and spongelike round microscopicparticles of cross-linked polymer beads (e.g., polystyrene or copolymersthereof), each defining a substantially noncollapsible pore network. TheMicrosponges can be loaded with an active ingredient and can provide acontrolled time release of the active ingredient to skin or to a mucosalmembrane upon application of the formulation. The slow release isintended to reduce irritation by the active. Microsponge® deliverytechnology was developed by Advanced Polymer Systems. In one or moreembodiments the composition comprisises one or more active agents loadedinto Microponges with a waterless carrier comprising a modulating agent.

Polymeric Agent

The composition of the present invention contains a polymeric agent. Ithas been documented that the presence of a polymeric agent is necessaryfor the creation of foam, having fine bubble structure, which does notreadily collapse upon release from the pressurized aerosol can. Thepolymeric agent serves to stabilize the foam composition and to controldrug residence in the target organ. Preferably, the polymeric agent issoluble or readily dispersible in the polyol; or in the mixture of apolyol and an additional polar solvent.

Non-limiting examples of polymeric agents that are soluble or readilydispersible in propylene glycol are Hydroxypropylcellulose and carbomer(homopolymer of acrylic acid is crosslinked with an allyl etherpentaerythritol, an allyl ether of sucrose, or an allyl ether ofpropylene, such as Carbopol® 934, Carbopol® 940, Carbopo® 941, Carbopol®980 and Carbopol® 981.

Other polymeric agents are suitable for use according to the presentinvention provided that they are soluble or readily dispersible in thepolyol; or in the mixture of a polyol and an additional polar solvent,on a case by case basis.

Exemplary polymeric agents include, in a non-limiting manner,naturally-occurring polymeric materials, such as locust bean gum, sodiumalginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum,sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guargum, cationic guars, hydroxypropyl guar gum, starch, amine-bearingpolymers such as chitosan; acidic polymers obtainable from naturalsources, such as alginic acid and hyaluronic acid; chemically modifiedstarches and the like, carboxyvinyl polymers, polyvinylpyrrolidone,polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acidpolymers, polyvinyl acetate polymers, polyvinyl chloride polymers,polyvinylidene chloride polymers and the like.

Additional exemplary polymeric agents include semi-synthetic polymericmaterials such as cellulose ethers, such as, hydroxypropyl cellulose,Polyethylene glycol, having molecular weight of 1000 or more (e.g., PEG1,000, PEG 4,000, PEG 6,000 and PEG 10,000) also have gelling capacityand while they are considered herein as “secondary polar solvents”, asdetailed herein, they are also considered polymeric agents.

Mixtures of the above polymeric agents are contemplated.

The concentration of the polymeric agent should be selected so that thecomposition, after filling into aerosol canisters, is flowable, and canbe shaken in the canister. In one or more embodiments, the concentrationof the polymeric agent is selected such that the viscosity of thecomposition, prior to filling of the composition into aerosol canisters,is less than 12,000 CPs, and more preferably, less than 10,000 CPs.

Surface-Active Agent

The composition further contains a surface-active agent. Surface-activeagents (also termed “surfactants”) include any agent linking oil andwater in the composition, in the form of emulsion. A surfactant'shydrophilic/lipophilic balance (HLB) describes the emulsifier's affinitytoward water or oil. HLB is defined for non-ionic surfactants. The HLBscale ranges from 1 (totally lipophilic) to 20 (totally hydrophilic),with 10 representing an equal balance of both characteristics.Lipophilic emulsifiers form water-in-oil (w/o) emulsions; hydrophilicsurfactants form oil-in-water (o/w) emulsions. The HLB of a blend of twoemulsifiers equals the weight fraction of emulsifier A times its HLBvalue plus the weight fraction of emulsifier B times its HLB value(weighted average). In many cases a single surfactant may suffice. Inother cases a combination of two or more surfactants is desired.Reference to a surfactant in the specification can also apply to acombination of surfactants or a surfactant system. As will beappreciated by a person skilled in the art which surfactant orsurfactant system is more appropriate is related to the vehicle andintended purpose. In general terms a combination of surfactants can besignificant in producing breakable forms of good quality. It has beenfurther discovered that the generally thought considerations for HLBvalues for selecting a surfactant or surfactant combination are notalways binding for emulsions and moreover for waterless andsubstantially non aqueous carriers the usual guidelines are lessapplicable. Surfactants also play a significant role in foam formationwhere the foamable formulation is a single phase composition.

According to one or more embodiments the composition contains a singlesurface active agent having an HLB value between about 2 and 9, or morethan one surface active agent and the weighted average of their HLBvalues is between about 2 and about 9.

According to one or more embodiments the composition contains a singlesurface active agent having an HLB value between about 7 and 14, or morethan one surface active agent and the weighted average of their HLBvalues is between about 7 and about 14.

According to one or more other embodiments the composition contains asingle surface active agent having an HLB value between about 9 andabout 19, or more than one surface active agent and the weighted averageof their HLB values is between about 9 and about 19.

In a waterless or substantially waterless environment a wide range ofHLB values may be suitable.

Preferably, the composition contains a non-ionic surfactant. Nonlimitingexamples of possible non-ionic surfactants include a polysorbate,polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20)sorbitan monooleate, a polyoxyethylene fatty acid ester, Myrj 45, Myrj49, Myrj 52 and Myrj 59; a polyoxyethylene alkyl ether, polyoxyethylenecetyl ether, polyoxyethylene palmityl ether, polyethylene oxidehexadecyl ether, polyethylene glycol cetyl ether, steareths such assteareth 2, brij 21, brij 721, brij 38, brij 52, brij 56 and brij W1, asucrose ester, a partial ester of sorbitol and its anhydrides, sorbitanmonolaurate, sorbitan monolaurate, a monoglyceride, a diglyceride,isoceteth-20 and mono-, di- and tri-esters of sucrose with fatty acids.In certain embodiments, suitable sucrose esters include those havinghigh monoester content, which have higher HLB values.

In an embodiment the surfactant is an ether for example polyoxyethylene(26) glycerol ether.

In certain embodiments, surfactants are selected which can provide aclose packed surfactant layer. To achieve such objectives combinationsof at least two surfactants are selected. Preferably, they should becomplex emulgators and more preferably they should both be of a similarmolecular type; for example, a pair of ethers, like steareth 2 andsteareth 21, or a pair of esters, for example, PEG-40 stearate andpolysorbate 80. Ideally, the surfactants can be ethers. In certaincircumstances POE esters cannot be used and a combination of sorbitanlaurate and sorbitan stearate or a combination of sucrose stearic acidester mixtures and sodium laurate may be used. All these combinationsdue to their versatility and strength may also be used satisfactorilyand effectively with ether frormulations, although the amounts andproportion may be varied according to the formulation and its objectivesas will be appreciated by a man of the art.

It has been discovered also that by using a derivatized hydrophilicpolymer with hydrophobic alkyl moieties as a polymeric emulsifier suchas pemulen it is possible to stabilize the emulsion better about or atthe region of phase reversal tension. Other types of derivatizedpolymers like silicone copolymers, derivatized starch [Aluminum StarchOctenylsuccinate (ASOS)]/[DRY-FLO AF Starch], and derivatized dexrin mayalso a similar stabilizing effect.

A series of dextrin derivative surfactants prepared by the reaction ofthe propylene glycol polyglucosides with a hydrophobicoxirane-containing material of the glycidyl ether are highlybiodegradable. [Hong-Rong Wang and Keng-Ming Chen, Colloids and SurfacesA: Physicochemical and Engineering Aspects Volume 281, Issues 1-3, 15Jun. 2006, Pages 190-193].

Non-limiting examples of non-ionic surfactants that have HLB of about 7to about 12 include steareth 2 (HLB-4.9); glyceryl monostearate/PEG 100stearate (Av HLB˜11.2); stearate Laureth 4 (HLB-9.7) and cetomacrogolether (e.g., polyethylene glycol 1000 monocetyl ether).

Non-limiting examples of preferred surfactants, which have a HLB of 4-19are set out in the Table below:

Surfactant HLB steareth 2 ~4.9 glyceryl monostearate/PEG 100 stearate Av~11.2 Glyceryl Stearate ~4 Steareth-21 ~15.5 peg 40 stearate ~16.9polysorbate 80 ~15 sorbitan stearate ~4.7 laureth 4 ~9.7 Sorbitanmonooleate (span 80) ~4.3 ceteareth 20 ~15.7 steareth 20 ~15.3 ceteth 20~15.7 Macrogol Cetostearyl Ether ~15.7 ceteth 2 (Lipocol C-2) ~5.3PEG-30 Dipolyhydroxystearate ~5.5 sucrose distearate (Sisterna SP30) ~6polyoxyethylene (100) stearate ~18.8

More exemplary stabilizing surfactants which may be suitable for use inthe present invention are found below.

PEG-Fatty Acid Monoester Surfactants Chemical name Product example nameHLB PEG-30 stearate Myrj 51 >10 PEG-40 laurate Crodet L40 (Croda) 17.9PEG-40 oleate Crodet O40 (Croda) 17.4 PEG-45 stearate Nikkol MYS-45(Nikko) 18 PEG-50 stearate Myrj 53 >10 PEG-100 stearate Myrj 59, Arlacel165 (ICI) 19

PEG-Fatty Acid Diester Surfactants: Chemical name Product example nameHLB PEG-4 dilaurate Mapeg .RTM. 200 DL (PPG), 7 Kessco .RTM.PEG 200 DL(Stepan), LIPOPEG 2-DL (Lipo Chem.) PEG-4 distearate Kessco .RTM. 200 5DS (Stepan.sub) PEG-32 dioleate Kessco .RTM. PEG 1540 DO 15 (Stepan)PEG-400 dioleate Cithrol 4DO series (Croda) >10 PEG-400 disterateCithrol 4DS series (Croda) >10 PEG-20 glyceryl oleate Tagat .RTM. O(Goldschmidt) >10

Transesterification Products of Oils and Alcohols Chemical name Productexample name HLB PEG-30 castor oil Emalex C-30 (Nihon Emulsion) 11PEG-40 hydrogenated Cremophor RH 40 (BASF), 13 castor oil Croduret(Croda), Emulgin HRE 40 (Henkel)

Polyglycerized Fatty Acids, such as: Chemical name Product example nameLB Polyglyceryl-6 dioleate Caprol .RTM. 6G20 (ABITEC); 8.5 PGO-62(Calgene), PLUROL OLEIQUE CC 497 (Gattefosse)Hodag

PEG-Sorbitan Fatty Acid Esters Chemical name Product example name HLBPEG-20 sorbitan Tween-20 (Atlas/ICI), Crillet 1 17 monolaurate (Croda),DACOL MLS 20 (Condea) PEG-20 sorbitan Tween 40 (Atlas/ICI), Crillet 2 16Monopalmitate (Croda) PEG-20 sorbitan Tween-60 (Atlas/ICI), Crillet 3 15monostearate (Croda) PEG-20 sorbitan Tween-80 (Atlas/ICI), Crillet 4 15monooleate (Croda)

Polyethylene Glycol Alkyl Ethers Chemical name Product example name HLBPEG-2 oleyl ether oleth-2 Brij 92/93 (Atlas/ICI) 4.9 PEG-3 oleyl etheroleth-3 Volpo 3 (Croda) <10 PEG-5 oleyl ether oleth-5 Volpo 5 (Croda)<10 PEG-10 oleyl ether oleth-10 Volpo 10 (Croda), Brij 12 96/97(Atlas/ICI) PEG-20 oleyl ether oleth-20 Volpo 20 (Croda), Brij 15 98/99(Atlas/ICI) PEG-4 lauryl ether laureth-4Brij 30 (Atlas/ICI) 9.7 PEG-23lauryl ether laureth-23Brij 35 (Atlas/ICI) 17 PEG-10 stearyl ether Brij76 (ICI) 12 PEG-2 cetyl ether Brij 52 (ICI) 5.3

Sugar Ester Surfactants Chemical name Product example name HLB Sucrosedistearate Sisterna SP50, Surfope 1811 11

Sorbitan Fatty Acid Ester Surfactants Chemical name Product example nameHLB Sorbitan monolaurate Span-20 (Atlas/ICI), Crill 1 8.6 (Croda),Arlacel 20 (ICI) Sorbitan monopalmitate Span-40 (Atlas/ICI), Crill 2 6.7(Croda), Nikkol SP-10 (Nikko) Sorbitan monooleate Span-80 (Atlas/ICI),Crill 4 4.3 (Croda), Crill 50 (Croda) Sorbitan monostearate Span-60(Atlas/ICI), Crill 3 4.7 (Croda), Nikkol SS-10 (Nikko)

In one or more embodiments the surface active agent is a complexemulgator in which the combination of two or more surface active agentscan be more effective than a single surfactant and provides a morestable formulation or improved foam quality than a single surfactant.For example and by way of non-limiting explanation it has been foundthat by choosing say two surfactants, one hydrophobic and the otherhydrophilic the combination can produce a more stable emulsion than asingle surfactant. Preferably, the complex emulgator comprises acombination of surfactants wherein there is a difference of about 4 ormore units between the HLB values of the two surfactants or there is asignificant difference in the chemical nature or structure of the two ormore surfactants.

Specific non limiting examples of surfactant systems are, combinationsof polyoxyethylene alkyl ethers, such as Brij 59/Brij 10; Brij 52/Brij10; Steareth 2/Steareth 20; Steareth 2/Steareth 21 (Brij 72/Brij 721);combinations of polyoxyethylene stearates such as Myrj 52/Myrj 59;combinations of sucrose esters, such as Surphope 1816/Surphope 1807;combinations of sorbitan esters, such as Span 20/Span 80; Span 20/Span60; combinations of sucrose esters and sorbitan esters, such as Surphope1811 and Span 60; combinations of liquid polysorbate detergents and PEGcompounds, such as Tween 80/PEG-40 stearate; methyl glucasosequistearate; polymeric emulsifiers, such as Permulen (TR1 or TR2);liquid crystal systems, such as Arlatone (2121), Stepan (Mild RM1),Nikomulese (41) and Montanov (68) and the like.

In certain embodiments the surfactant is preferably one or more of thefollowing: a combination of steareth-2 and steareth-21 on their own orin combination with glyceryl monostearate (GMS); in certain otherembodiments the surfactant is a combination of polysorbate 80 and PEG-40stearate. In certain other embodiments the surfactant is a combinationof glyceryl monostearate/PEG 100 stearate. In certain other embodimentsthe surfactant is a combination of two or more of stearate 21, PEG 40stearate, and polysorbate 80. In certain other embodiments thesurfactant is a combination of two or more of laureth 4, span80, andpolysorbate 80. In certain other embodiments the surfactant is acombination of two or more of GMS and ceteareth. In certain otherembodiments the surfactant is a combination of two or more of steareth21, ceteareth 20, ceteth 2 and laureth 4 In certain other embodimentsthe surfactant is a combination of ceteareth 20 and polysorbate 40stearate. In certain orther embodiments the surfactant is a combinationof span 60 and GMS. In certain other embodiments the surfactant is acombination of two or all of PEG 40 stearate, sorbitan stearate andpolysorbate 60

In certain other embodiments the surfactant is one or more of sucrosestearic acid esters, sorbitan laureth, and sorbitan stearate.

Without being bound by any particular theory or mode of operation, it isbelieved that the use of non-ionic surfactants with significanthydrophobic and hydrophilic components, increase the emulsifier or foamstabilization characteristics of the composition. Similarly, withoutbeing bound by any particular theory or mode of operation, usingcombinations of surfactants with high and low HLB's to provide arelatively close packed surfactant layer may strengthen the formulation.

In one or more embodiments the stability of the composition can beimproved when a combination of at least one non-ionic surfactant havingHLB of less than 9 and at least one non-ionic surfactant having HLB ofequal or more than 9 is employed. The ratio between the at least onenon-ionic surfactant having HLB of less than 9 and the at least onenon-ionic surfactant having HLB of equal or more than 9, is between 1:8and 8:1, or at a ratio of 4:1 to 1:4. The resultant HLB of such a blendof at least two emulsifiers is preferably between about 9 and about 14.

Thus, in an exemplary embodiment, a combination of at least onenon-ionic surfactant having HLB of less than 9 and at least onenon-ionic surfactant having HLB of equal or more than 9 is employed, ata ratio of between 1:8 and 8:1, or at a ratio of 4:1 to 1:4, wherein theHLB of the combination of emulsifiers is preferably between about 5 andabout 18.

In certain cases, the surface active agent is selected from the group ofcationic, zwitterionic, amphoteric and ampholytic surfactants, such assodium methyl cocoyl taurate, sodium methyl oleoyl taurate, sodiumlauryl sulfate, triethanolamine lauryl sulfate and betaines.

Many amphiphilic molecules can show lyotropic liquid-crystalline phasesequences depending on the volume balances between the hydrophilic partand hydrophobic part. These structures are formed through themicro-phase segregation of two Many amphiphilic molecules can showlyotropic liquid-crystalline phase sequences depending on the volumebalances between the hydrophilic part and hydrophobic part. Thesestructures are formed through the micro-phase segregation of twoincompatible components on a nanometer scale. Soap is an everydayexample of a lyotropic liquid crystal. Certain types of surfactants tendto form lyotropic liquid crystals in emulsions interface (oil-in-water)and exert a stabilizing effect

In one or more embodiments the surfactant is a surfactant or surfactantcombination is capable of or which tends to form liquid crystals.Surfactants which tend to form liquid crystals may improve the qualityof foams. Non limiting examples of surfactants with postulated tendencyto form interfacial liquid crystals are: phospholipids, alkylglucosides, sucrose esters, sorbitan esters.

In one or more embodiments the at least one surface active agent isliquid. Moreover for the purposes of formulating with liquid ethers aliquid surfactant is preferred

In one or more embodiments the liquid surfactant is a polysorbate,preferably polysorbate 80 or 60.

In one or more embodiments the at least one surface active agent issolid, semi solid or waxy. In a further embodiment they are soluble inoil and in another embodiment have a HLB of less than about 12.

It should be noted that HLB values may not be so applicable to non ionicsurfactants, for example, with liquid crystals or with silicones. AlsoHLB values may be of lesser significance in a waterless or substantiallynon-aqueous environment.

In one or more embodiments the surfactant can be, a surfactant systemcomprising of a surfactant and a co surfactant, a waxy emulsifier, aliquid crystal emulsifier, an emulsifier which is solid or semi solid atroom temperature and pressure, or combinations of two or more agents inan appropriate proportion as will be appreciated a person skilled in theart. Where a solid or semi solid emulsifier combination is used it canalso comprise a solid or semi solid emulsifier and a liquid emulsifier.In a preferred embodiment at least one surfactant is a liquid.

In one or more embodiments, the surface-active agent includes at leastone non-ionic surfactant. Ionic surfactants are known to be irritants.Therefore, non-ionic surfactants are preferred in applications includingsensitive tissue such as found in most mucosal tissues, especially whenthey are infected or inflamed. Non-ionic surfactants alone can provideformulations and foams of good or excellent quality in the carriers andcompositions of the present invention.

Thus, in a preferred embodiment, the surface active agent, thecomposition contains a non-ionic surfactant. In another preferredembodiment the composition includes a mixture of non-ionic surfactantsas the sole surface active agent. Yet, in additional embodiments, thefoamable composition includes a mixture of at least one non-ionicsurfactant and at least one ionic surfactant in a ratio in the range ofabout 100:1 to 6:1. In one or more embodiments, the non-ionic to ionicsurfactant ratio is greater than about 6:1, or greater than about 8:1;or greater than about 14:1, or greater than about 16:1, or greater thanabout 20:1. In further embodiments, surface active agent comprises acombination of a non-ionic surfactant and an ionic surfactant, at aratio of between 1:1 and 20:1

In one or more embodiments, a combination of a non-ionic surfactant andan ionic surfactant (such as sodium lauryl sulphate andcocamidopropylbetaine) is employed, at a ratio of between 1:1 and 20:1,or at a ratio of 4:1 to 10:1; for example, about 1:1, about 4:1, about8:1, about 12:1, about 16:1 and about 20:1 or at a ratio of 4:1 to 10:1,for example, about 4:1, about 6:1, about 8:1 and about 10:1.

For foams in selecting a suitable surfactant or combination thereof itshould be borne in mind that the upper amount of surfactant that may beused may be limited by the shakability of the composition. If thesurfactant is non liquid, it can make the formulation to viscous orsolid. Subject to its miscibily solid surfactants may be added first,and may require gentle warming and then cooling before being combinedwith the other ingredients. In general terms, as the amount ofnon-liquid surfactant is increased the shakability of the formulationreduces until a limitation point is reached where the formulation canbecome non shakable and unsuitable. Thus in one embodiment, anyeffective amount of surfactant may be used provided the formulationremains shakable. In other certain limited embodiments the upper limitfor foamable formulations may be determined by flowability such that anyeffective amount can be used provided the formulation is sufficientlyflowable to be able to flow through an actuator valve and be releasedand still expand to form a good quality foam. This may be due withoutbeing bound by any theory to one or more of a number of factors such asthe viscosity, the softness, the lack of crystals, the pseudoplastic orsemi pseudo plastic nature of the composition and the dissolution of thepropellant into the composition.

In certain embodiments the amount of surfactant or combination ofsurfactants is between about 0.05% to about 20%; between about 0.05% toabout 15%. or between about 0.05% to about 10%. In a preferredembodiment the concentration of surface active agent is between about0.2% and about 8%. In a more preferred embodiments the concentration ofsurface active agent is between about 1% and about 6% or between about1% and about 4%.

In some embodiments, it is desirable that the surface active agent doesnot contain a polyoxyethylene (POE) moiety, such as polysorbatesurfactants, POE fatty acid esters, and POE alkyl ethers, because theactive agent is incompatible with such surface active agents. Forexample, the active agent pimecrolimus is not stable the presence of POEmoieties, yet benefits greatly from the use of dicarboxylic esters aspenetration enhancers. In such cases, alternative surface active agentsare employed. In an exemplary manner, POE—free surfactants includenon-ethoxylated sorbitan esters, such as sorbitan monopalmitate,sorbitan monostearate, sorbitan tristearate, sorbitan monooleate,sorbitan trioleate, sorbitan monolaurate and sorbitan sesquioleate;glycerol fatty acid esters, such as glycerol monostearate and glycerolmonooleate; mono-, di- and tri-esters of sucrose with fatty acids(sucrose esters), sucrose stearate, sucrose distearate sucrose palmitateand sucrose laurate; and alkyl polyglycosides, such as lauryldiglucoside.

In one or more embodiments, the surface-active agent includes mono-, di-and tri-esters of sucrose with fatty acids (sucrose esters), preparedfrom sucrose and esters of fatty acids or by extraction fromsucro-glycerides. Suitable sucrose esters include those having highmonoester content, which have higher HLB values.

In one or more preferred embodiments of the present invention thesurfactant includes at least one surfactant selected from apolyoxyethylene fatty ether, a polyoxyethylene fatty ester, acarbohydrate ester and a sucrose ester.

In one or more embodiments non limiting examples of non-ionicsurfactants include steareth-2, steareth-20, steareth-21, ceteareth 2,PEG-100 stearyl ether, cetearyl glucoside, methyl glucosesesquistearate, sorbitan monostearate, GMS NE and span 20.

In one or more embodiments non limiting other examples of surfactantcombinations are glyceryl stearate and PEG 100 stearate and laureth4;steareth 2, PEG 100 searate and laureth4; and cetearyl glucoside andcetearyl alcohol.

In an embodiment the surfactant containing formulations are furtherboosted by a foam adjuvant for example stearyl alcohol.

A non limiting example of a combination of surfactants having a weightedaverage of their HLB values of 11 is Glyceryl Stearate and PEG-100Stearate (for example trade name “simulsol 165” from Sepic).

Hydrophobic Solvent

Optionally, the foamable carrier further contains at least onehydrophobic solvent. The identification of a “hydrophobic solvent”, asused herein, is not intended to characterize the solubilizationcapabilities of the solvent for any specific active agent or any othercomponent of the foamable composition. Rather, such information isprovided to aid in the identification of materials suitable for use as apart in the foamable compositions described herein.

A “hydrophobic solvent” as used herein refers to a material havingsolubility in distilled water at ambient temperature of less than about1 gm per 100 mL, more preferable less than about 0.5 gm per 100 mL, andmost preferably less than about 0.1 gm per 100 mL.

In one or more embodiments, the hydrophobic organic carrier is an oil,such as mineral oil, isopropyl palmitate, isopropyl isostearate,diisopropyl adipate, diisopropyl dimerate, maleated soybean oil, octylpalmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate,acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryloleate, tocopheryl linoleate, wheat germ glycerides, arachidylpropionate, myristyl lactate, decyl oleate, propylene glycolricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate,neopentylglycol dicaprylate/dicaprate, isononyl isononanoate,isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyldodecanol, unsaturated or polyunsaturated oils, such as olive oil, cornoil, soybean oil, canola oil, cottonseed oil, coconut oil, sesame oil,sunflower oil, borage seed oil, syzigium aromaticum oil, hempseed oil,herring oil, cod-liver oil, salmon oil, flaxseed oil, wheat germ oil,evening primrose oils; essential oils; and silicone oils, such asdimethicone, cyclomethicone, polyalkyl siloxanes, polyaryl siloxanes,polyalkylaryl siloxanes and polyether siloxane copolymers,polydimethylsiloxanes (dimethicones) andpoly(dimethylsiloxane)-(diphenyl-siloxane) copolymers. In one or morefurther embodiments the hydrophobic organic carrier is petrolatum.

Humectant

A humectant, is a substance that helps retain moisture and also preventsrapid evaporation. Non limiting examples of suitable heumectants arepropylene glycol, propylene glycol derivatives, and glycerin. Otherexamples of humectants and moisturizers may be found in the Handbook ofPharmaceutical Additives published by Gower. Suitable ones for use withand soluble in the waterless compositions of the present invention maybe selected as will be appreciated by a person skilled in the art.

Moisturizers

A moisturizer, is a substance that helps retain moisture or add backmoisture to the skin. Examples are allantoin, petrolatum, urea, lacticacid, sodium PCV, glycerin, shea butter, caprylic/capric/stearictriglyceride, candelilla wax, propylene glycol, lanolin, hydrogenatedoils, squalene, sodium hyaluronate and lysine PCA. Glycerine and sodiumpCA work in combination. Other examples may be found in the Handbook ofPharmaceutical Additives published by Gower.

Pharmaceutical compositions of the present invention may in one or moreembodiments usefully comprise in addition a humectant or a moisturizeror combinations thereof.

Foam Adjuvant

Optionally, a foam adjuvant is included in the foamable carriers of thepresent invention to increase the foaming capacity of surfactants and/orto stabilize the foam. In one or more embodiments of the presentinvention, the foam adjuvant agent includes fatty alcohols having 15 ormore carbons in their carbon chain, such as cetyl alcohol and stearylalcohol (or mixtures thereof). Other examples of fatty alcohols arearachidyl alcohol (C20), behenyl alcohol (C22), 1-triacontanol (C30), aswell as alcohols with longer carbon chains (up to C50). Fatty alcohols,derived from beeswax and including a mixture of alcohols, a majority ofwhich has at least 20 carbon atoms in their carbon chain, are especiallywell suited as foam adjuvant agents. The amount of the fatty alcoholrequired to support the foam system is inversely related to the lengthof its carbon chains. Foam adjuvants, as defined herein are also usefulin facilitating improved spreadability and absorption of thecomposition.

In one or more embodiments of the present invention, the foam adjuvantagent includes fatty acids having 16 or more carbons in their carbonchain, such as hexadecanoic acid (C16) stearic acid (C18), arachidicacid (C20), behenic acid (C22), octacosanoic acid (C28), as well asfatty acids with longer carbon chains (up to C50), or mixtures thereof.As for fatty alcohols, the amount of fatty acids required to support thefoam system is inversely related to the length of its carbon chain.

Optionally, the carbon atom chain of the fatty alcohol or the fatty acidmay have at least one double bond. A further class of foam adjuvantagent includes a branched fatty alcohol or fatty acid. The carbon chainof the fatty acid or fatty alcohol also can be substituted with ahydroxyl group, such as 12-hydroxy stearic acid.

Additional Components

In an embodiment of the present invention, a composition of the presentinvention includes one or more additional components. Such additionalcomponents include but are not limited to anti perspirants, anti-staticagents, buffering agents, bulking agents, chelating agents, cleansers,colorants, conditioners, deodorants, diluents, dyes, emollients,fragrances, hair conditioners, humectants, pearlescent aids, perfumingagents, permeation enhancers, pH-adjusting agents, preservatives,protectants, skin penetration enhancers, softeners, solubilizers,sunscreens, sun blocking agents, sunless tanning agents, viscositymodifiers and vitamins and flavonoids. As is known to one skilled in theart, in some instances a specific additional component may have morethan one activity, function or effect.

In an embodiment of the present invention, the additional component is apH adjusting agent or a buffering agent. Suitable buffering agentsinclude but are not limited to acetic acid, adipic acid, calciumhydroxide, citric acid, glycine, hydrochloric acid, lactic acid,magnesium aluminometasilicates, phosphoric acid, sodium carbonate,sodium citrate, sodium hydroxide, sorbic acid, succinic acid, tartaricacid, and derivatives, salts and mixtures thereof.

In an embodiment of the present invention, the additional component isan emollient. Suitable emollients include but are not limited to mineraloil, lanolin oil, coconut oil, cocoa butter, olive oil, aloe veraextract, jojoba oil, castor oil, fatty acids, fatty alcohols,diisopropyl adipate, hydroxybenzoate esters, benzoic acid esters of C9to C15 alcohols, isononyl iso-nonanoate, silicone oils, polyethers, C12to C15 alkyl benzoates, oleic acid, stearic fatty acid, cetyl alcohols,hexadecyl alcohol, dimethyl polysiloxane, polyoxypropylene cetyl ether,polyoxypropylene butyl ether, and derivatives, esters, salts andmixtures thereof.

In an embodiment of the present invention, the additional component is ahumectant. Suitable humectants include but are not limited to guanidine,urea, glycolic acid, glycolate salts, ammonium glycolate, quaternaryalkyl ammonium glycolate, lactic acid, lactate salts, ammonium lactate,quaternary alkyl ammonium lactate, aloe vera, aloe vera gel, allantoin,urazole, alkoxylated glucose, hyaluronic acid, lactamidemonoethanolamine, acetamide monoethanolamine and derivatives, esters,salts and mixtures thereof.

In an embodiment of the present invention, the additional component is apreservative. Suitable preservatives include but are not limited to C12to C15 alkyl benzoates, alkyl p-hydroxybenzoates, aloe vera extract,ascorbic acid, benzalkonium chloride, benzoic acid, benzoic acid estersof C9 to C15 alcohols, butylated hydroxytoluene, castor oil, cetylalcohols, chlorocresol, citric acid, cocoa butter, coconut oil,diazolidinyl urea, diisopropyl adipate, dimethyl polysiloxane, DMDMhydantoin, ethanol, fatty acids, fatty alcohols, hexadecyl alcohol,hydroxybenzoate esters, iodopropynyl butylcarbamate, isononyliso-nonanoate, jojoba oil, lanolin oil, methylparaben, mineral oil,oleic acid, olive oil, polyethers, polyoxypropylene butyl ether,polyoxypropylene cetyl ether, potassium sorbate, silicone oils, sodiumpropionate, sodium benzoate, sodium bisulfite, sorbic acid, stearicfatty acid, vitamin E, vitamin E acetate and derivatives, esters, saltsand mixtures thereof.

In an embodiment of the present invention, the additional component is askin penetration enhancer. Suitable skin penetration enhancers includebut are not limited to acetone, acyl lactylates, acyl peptides,acylsarcosinates, alkanolamine salts of fatty acids, alkyl benzenesulphonates, alkyl ether sulphates, alkyl sulphates, anionicsurface-active agents, benzyl benzoate, benzyl salicylate,butan-1,4-diol, butyl benzoate, butyl laurate, butyl myristate, butylstearate, cationic surface-active agents, citric acid,cocoamidopropylbetaine, decyl methyl sulfoxide, decyl oleate, dibutylazelate, dibutyl phthalate, dibenzyl sebacate, dibutyl sebacate, dibutylsuberate, dibutyl succinate, dicapryl adipate, didecyl phthalate,diethylene glycol, diethyl sebacate, diethyl-m-toluamide,di(2-hydroxypropyl)ether, diisopropyl adipate, diisopropyl sebacate,N,N-dimethyl acetamide, dimethyl azelate, N,N-dimethyl formamide,1,5-dimethyl-2-pyrrolidone, dimethyl sebacate, dimethyl sulphoxide,dioctyl adipate, dioctyl azelate, dioctyl sebacate, 1,4 dioxane,1-dodecylazacyloheptan-2-one, dodecyl dimethyl amine oxides, ethylcaprate, ethyl caproate, ethyl caprylate, 2-ethyl-hexyl pelargonate,ethyl-2-hydroxypropanoate, ethyl laurate, ethyl myristate,1-ethyl-2-pyrrolidone, ethyl salicylate, hexyl laurate,2-hydroxyoctanoic acid, 2-hydroxypropanoic acid, 2-hydroxypropionicacid, isethionates, isopropyl isostearate, isopropyl palmitate, guarhydroxypropyltrimonium chloride, hexan-2,5-diol, khellin, lamepons,lauryl alcohol, maypons, metal salts of fatty acids, methyl nicotinate,2-methyl propan-2-ol, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,methyl taurides, miranol, nonionic surface-active agents, octyl alcohol,octylphenoxy polyethoxyethanol, oleic ethanolamide, pleyl alcohol,pentan-2,4-diol, phenoxyethanol, phosphatidyl choline, phosphine oxides,polyalkoxylated ether glycollates, poly(diallylpiperidinium chloride),poly(dipropyldiallylammonium chloride), polyglycerol esters,polyoxyethylene lauryl ether, polyoxy:polyoxyethylene stearate,polyoxypropylene 15 stearyl ether, poly(vinyl pyridinium chloride),propan-1-ol, propan-2-ol, propylene glycol dipelargonate, pyroglutamicacids, 2-pyrrolidone, pyruvic acids, Quaternium 5, Quaternium 18,Quaternium 19, Quaternium 23, Quaternium 31, Quaternium 40, Quaternium57, quartenary amine salts, quaternised poly(dimethylaminoethylmethacrylate), quaternised poly (vinyl alcohol),sapamin hydrochloride, sodium cocaminopropionate, sodium dioctylsulphonsuccinate, sodium laurate, sodium lauryl ether sulphate, sodiumlauryl sulphate, sugar esters, sulphosuccinate, tetrahydrofuran,tetrahydrofurfural alcohol, transcutol, triethanolamine dodecyl benzenesulphonate, triethanolamine oleate, urea, water and derivatives, esters,salts and mixtures thereof.

In an embodiment the composition with modulating agent may be used as iswithout addition of a propellant. In other embodiments propellant isadded to form a foamable composition that produces a foam when theformulation is expelled from a pressurized canister. The foam may be ofvarious qualities as indicated herein. In a preferred embodiment thefoam is of about good quality. In a more preferred embodiment it is ofabout excellent quality.

Propellants

Examples of suitable propellants include volatile hydrocarbons such asbutane, propane, isobutane and fluorocarbon gases, or mixtures thereof.

In an embodiment the propellant is AP 70 which is a mixture of propane,isobutene and butane.

The propellant makes up about 5-25 wt % of the foamable composition. Insome circumstances the propellant may be upto 35%. The propellants areused to generate and administer the foamable composition as a foam. Thetotal composition including propellant, foamable compositions andoptional ingredients is referred to as the foamable composition.

Alcohol and organic solvents render foams inflammable. It has beensurprisingly discovered that fluorohydrocarbon propellants, other thanchloro-fluoro carbons (CMCs), which are non-ozone-depleting propellants,are particularly useful in the production of a non-flammable foamablecomposition. A test according to European Standard prEN 14851, titled“Aerosol containers—Aerosol foam flammability test” revealed thatcompositions containing an organic carrier that contains a hydrophobicorganic carrier and/or a polar solvent, which are detected asinflammable when a hydrocarbon propellant is used, become non-flammable,while the propellant is an HFC propellant.

Such propellants include, but are not limited to, hydrofluorocarbon(HFC) propellants, which contain no chlorine atoms, and as such, fallcompletely outside concerns about stratospheric ozone destruction bychlorofluorocarbons or other chlorinated hydrocarbons. Exemplarynon-flammable propellants according to this aspect of the inventioninclude propellants made by DuPont under the registered trademark Dymel,such as 1,1,1,2 tetrafluorethane (Dymel 134), and 1,1,1,2,3,3,3heptafluoropropane (Dymel 227) 1,1, difluoro ethane (Dymel 152) and1,1,1,3,3,3 hexafluoropropane HFCs possess Ozone Depletion Potential of0.00 and thus, they are allowed for use as propellant in aerosolproducts.

Notably, the stability of foamable emulsions including HFC as thepropellant can be improved in comparison with the same composition madewith a hydrocarbon propellant.

In one or more embodiments foamable compositions comprise a combinationof a HFC and a hydrocarbon propellant such as n-butane or mixtures ofhydrocarbon propellants such as propane, isobutane and butane.

Composition and Foam Physical Characteristics and Advantages

A pharmaceutical or cosmetic composition manufactured using the foamablecarrier of the present invention is very easy to use. When applied ontothe afflicted body surface of mammals, i.e., humans or animals, it is ina foam state, allowing free application without spillage. Upon furtherapplication of a mechanical force, e.g., by rubbing the composition ontothe body surface, it freely spreads on the surface and is rapidlyabsorbed.

The foamable composition of the present invention is stable, having anacceptable shelf-life of months or preferably at least one year, or morepreferably, at least two years at ambient temperature, as revealed inaccelerated stability tests. Organic carriers and propellants tend toimpair the stability of emulsions and to interfere with the formation ofstable foam upon release from a pressurized container. It has beenobserved, however, that the foamable compositions according to thepresent invention are surprisingly stable. Following acceleratedstability studies, they demonstrate desirable texture; they form finebubble structures that do not break immediately upon contact with asurface, spread easily on the treated area and absorb quickly.

The composition should also be free flowing, to allow it to flow throughthe aperture of the container, e.g., and aerosol container, and createan acceptable foam.

Foam quality can be graded as follows:

Grade E (excellent): very rich and creamy in appearance, does not showany bubble structure or shows a very fine (small) bubble structure; doesnot rapidly become dull; upon spreading on the skin, the foam retainsthe creaminess property and does not appear watery.

Grade G (good): rich and creamy in appearance, very small bubble size,“dulls” more rapidly than an excellent foam, retains creaminess uponspreading on the skin, and does not become watery.

Grade FG (fairly good): a moderate amount of creaminess noticeable,bubble structure is noticeable; upon spreading on the skin the productdulls rapidly and becomes somewhat lower in apparent viscosity.

Grade F (fair): very little creaminess noticeable, larger bubblestructure than a “fairly good” foam, upon spreading on the skin itbecomes thin in appearance and watery.

Grade P (poor): no creaminess noticeable, large bubble structure, andwhen spread on the skin it becomes very thin and watery in appearance.

Grade VP (very poor): dry foam, large very dull bubbles, difficult tospread on the skin.

Topically administrable foams are typically of quality grade E or G,when released from the aerosol container. Smaller bubbles are indicativeof more stable foam, which does not collapse spontaneously immediatelyupon discharge from the container. The finer foam structure looks andfeels smoother, thus increasing its usability and appeal.

A further aspect of the foam is breakability. Thermally sensitive foamsimmediately collapse upon exposure to skin temperature and, therefore,cannot be applied on the hand and afterwards delivered to the afflictedarea.

The foam of the present invention has several advantages, when comparedwith hydroalcoholic foam compositions, such as

-   (1) Breakability. The foam of the present invention is thermally    stable and breakable under sheer force but is not “quick breaking    which allows comfortable application and well directed    administration to the target area;-   (2) Skin drying and skin barrier function. Short chain alcohols are    known to dry the skin and impair the integrity of the skin barrier.    By contrast, including a film forming agent in the composition of    the present invention foes not cause unwanted skin barrier damage;    and-   (3) Irritability. Due to the lack of alcohol and improvement in skin    barrier function, skin irritability is eliminated or reduced.

Another property of the foam is specific gravity, as measured uponrelease from the aerosol can. Typically, foams have specific gravity ofless than 0.12 g/mL; or less than 0.10 g/mL; or less than 0.08 g/mL,depending on their composition and on the propellant concentration.

Pharmaceutical Composition

The compositions, the foamable compositions and the foams of the presentinvention are ideal vehicles for active pharmaceutical ingredients andactive cosmetic ingredients. In the context of the present invention,active pharmaceutical ingredients and active cosmetic ingredients arecollectively termed “active agent” or “active agents”. A foamablecomposition, comprising an active agent has the following advantages:

-   -   1. The foamable composition provides a preferred solvent for        active agents, particularly water-insoluble agents.    -   2. The inclusion of a polyol and/or a PEG and a secondary polar        solvent in the foamable composition facilitates a co-solvent        effect, resulting increased concentrations of soluble active        agent in the dosage form, thus facilitating enhanced skin        penetration of the active agent. In many cases, increased        penetration is positively correlated with improved clinical        outcome. In certain case, attaining an increased drug        penetration into the target site of action enables a decrease of        treatment frequency, for example, from twice or three times        daily to once daily.    -   3. Polyols and PEGs; and combinations of a polyol and/or PEG        with a secondary polar solvent are known as skin penetration        enhancers, thus, increasing drug residence in the target area        and increasing clinical efficacy, as detailed above.    -   4. The fact that the compositions contains no water, or merely        up to 5% and water minimizes the probability of degradation of        water-sensitive active agents. Furthermore, as exemplified        herein, a foam containing a polyol and/or PEG with no water at        all can be formed in accordance with the composition and process        of the present invention. Such compositions ensure high        stability of water sensitive active agents.    -   5. Combining the anti-infective effect of a water-free, thus        hygroscopic composition, which acts through a dehydration        mechanism, with an additional anti-infective agent, selected        from the group of an antibiotic agent, an antibacterial agent,        an antifungal agent, an agent that controls yeast, an antiviral        agent and an antiparasitic agent, that acts through alternate        mechanisms results in a synergistic effect and consequently        higher success rate of the treatment.    -   6. The foamable polyol composition in contained in an        impermeable pressurized packaging presentation is impermeable        and thus, the active agent is not exposed to environmental        degradation factors, such as light and oxidating agent during        storage.

Thus, in a preferred embodiment of the present invention, thecomposition includes at least one active agent.

-   -   a. a therapeutically effective concentration of an active agent;    -   b. a modulating agent;    -   c. about 50% to about 98% of a polar solvent, selected from the        group consisting of a polyol and a polyethylene glycol;    -   d. 0% to about 48% of a secondary polar solvent;    -   e. about 0.2% to about 5% by weight of a surface-active agent;    -   f. about 0.01% to about 5% by weight of at least one polymeric        agent; and for a foamable composition additionally    -   g. a liquefied or compressed gas propellant at a concentration        of about 3% to about 25% by weight of the total composition.        wherein the composition is stored in an aerosol container and        upon release expands to form a breakable foam.

Active Agents

Suitable active agents include but are not limited to active herbalextracts, acaricides, age spot and keratose removing agents, allergen,analgesics, local anesthetics, antiacne agents, antiallergic agents,antiaging agents, antibacterials, antibiotics, antiburn agents,anticancer agents, antidandruff agents, antidepressants, antidermatitisagents, antiedemics, antihistamines, antihelminths, antihyperkeratolyteagents, antiinflammatory agents, antiirritants, antilipemics,antimicrobials, antimycotics, antiproliferative agents, antioxidants,anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosaceaagents antiseborrheic agents, antiseptic, antiswelling agents, antiviralagents, antiyeast agents, astringents, topical cardiovascular agents,chemotherapeutic agents, corticosteroids, dicarboxylic acids,disinfectants, fungicides, hair growth regulators, hormones, hydroxyacids, immunosuppressants, immunoregulating agents, insecticides, insectrepellents, keratolytic agents, lactams, metals, metal oxides,mitocides, neuropeptides, non-steroidal anti-inflammatory agents,oxidizing agents, pediculicides, photodynamic therapy agents, retinoids,sanatives, scabicides, self tanning agents, skin whitening agents,asoconstrictors, vasodilators, vitamins, vitamin D derivatives,flavonoids, wound healing agents and wart removers. As is known to oneskilled in the art, in some instances a specific active agent may havemore than one activity, function or effect.

In an embodiment of the present invention, the active agent is an activeherbal extract. Suitable active herbal extracts include but are notlimited to angelica, anise oil, astragali radix, azalea, benzyl acetate,birch tar oil, bornyl acetate, cacumen biotae, camphor, cantharidin,capsicum, cineole, cinnamon bark, cinnamon leaf, citronella,citroneliol, citronellyl acetate, citronellyl formate, eucalyptus,eugenyl acetate, flos carthami, fructus mori, garlic, geraniol,geranium, geranyl acetate, habanera, isobutyl angelicate, lavender,ledum latifolium, ledum palustre, lemongrass, limonene, linalool,linalyl acetate, methyl anthranilate, methyl cinnamate, mezereum, neem,nerol, neryl acetate, nettle root extract, oleum ricini, oregano,pinenes, .alpha.-pinene, .beta.-pinene, radix angelicae sinesis, radixpaenoiae rubra, radix polygoni multiflori, radix rehmanniae, rhizomapinelliae, rhizoma zingiberis recens, sabadilla, sage, sandalwood oil,saw palmetto extract, semen sesami nigrum, staphysagria, tea tree oil,terpene alcohols, terpene hydrocarbons, terpene esters, terpinene,terpineol, terpinyl acetate and derivatives, esters, salts and mixturesthereof. In an embodiment of the present invention, the active agent isan acaricide. Suitable acaricides include but are not limited toamitraz, flumethrin, fluvalinate and derivatives, esters, salts andmixtures thereof.

In an embodiment of the present invention, the active agent is an agespot and keratoses removing agent. Suitable age spot and keratosesremoving agent include but are not limited to hydroxy acids, azelaicacid and other related dicarboxylic acids, retinoids, kojic acid,arbutin, nicotinic, ascorbic acid, hydroquinone and derivatives, esters,salts and mixtures thereof. Certain nonsteroidal anti-inflammatoryagents, such as diclofenac are also useful for the treatment ofkeratoses.

In an embodiment of the present invention, the active agent is ananalgesic. Suitable analgesics include but are not limited tobenzocaine, butamben picrate, dibucaine, dimethisoquin, dyclonine,lidocaine, pramoxine, tetracaine, salicylates and derivatives, esters,salts and mixtures thereof.

In an embodiment of the present invention, the active agent is a localanesthetic. Suitable local anesthetics include but are not limited tobenzocaine, benzyl alcohol, bupivacaine, butamben picrate,chlorprocaine, cocaine, dibucaine, dimethisoquin, dyclonine, etidocaine,hexylcaine, ketamine, lidocaine, mepivacaine, phenol, pramoxine,procaine, tetracaine, salicylates and derivatives, esters, salts andmixtures thereof.

In an embodiment of the present invention, the active agent is anantiacne agent. Suitable antiacne agents include but are not limited toN-acetylcysteine, adapalene, azelaic acid, benzoyl peroxide, cholate,clindamycin, deoxycholate, erythromycin, flavinoids, glycolic acid,meclocycline, metronidazol, mupirocin, octopirox, phenoxy ethanol,phenoxy proponol, pyruvic acid, resorcinol, retinoic acid, salicylicacid, scymnol sulfate, sulfacetamide-sulfur, sulfur, tazarotene,tetracycline, tretinoin triclosan and derivatives, esters, salts andmixtures thereof.

In an embodiment of the present invention, the active agent is anantiaging agent. Suitable antiaging agents include but are not limitedto sulfur-containing D and L amino acids, alpha-hydroxy acids s,beta-hydroxy acids (e.g. salicylic acid), urea, hyaluronic acid, phyticacid, lipoic acid; lysophosphatidic acid, skin peel agents (e.g.,phenol, resorcinol and the like), vitamin B3 compounds (e.g.,niacinamide, nicotinic acid and nicotinic acid salts and esters,including non-vasodilating esters of nicotinic acid (such as tocopherylnicotinate), nicotinyl amino acids, nicotinyl alcohol esters ofcarboxylic acids, nicotinic acid N-oxide and niacinamide N-oxide),vitamin B5 and retinoids (e.g., retinol, retinal, retinoic acid, retinylacetate, retinyl palmitate, retinyl ascorbate) skin barrier formingagents, melatonin and derivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is anantibiotic. The terms “antibiotic” as used herein shall include, but isnot limited to, any substance being destructive to or inhibiting thegrowth of bacteria or any substance having the capacity to inhibit thegrowth of or to destroy bacteria. In one or more embodiments, theantibiotic agent is selected from the group consisting of a beta-lactamantibiotic, an aminoglycoside, an ansa-type antibiotic, ananthraquinone, an azole, an antibiotic glycopeptide, a macrolide, anantibiotic nucleoside, an antibiotic peptide, an antibiotic polyene, anantibiotic polyether, an antibiotic quinolone, an antibiotic steroid, asulfonamide, an antibiotic metal, an oxidizing agent, a periodate, ahypochlorite, a permanganate, a substance that release free radicalsand/or active oxygen, a cationic antimicrobial agent, a quaternaryammonium compound, a biguanide, a triguanide, a bisbiguanide, apolymeric biguanide, and analogs, derivatives, salts, ions and complexesthereof.

Suitable antibiotics include but are not limited to amanfadinehydrochloride, amanfadine sulfate, amikacin, arnikacin sulfate,aminoglycosides, amoxicillin, ampicillin, ansamycins, bacitracin,beta-lactams, candicidin, capreomycin, carbenicillin, cephalexin,cephaloridine, cephalothin, cefazolin, cephapirin, cephradine,cephaloglycin, chloramphenicols, chlorhexidine, chlorhexidine gluconate,chlorhexidine hydrochloride, chloroxine, chlorquinaldol,chlortetracycline, chlortetracycline hydrochloride, ciprofloxacin,circulin, clindamycin, clindamycin hydrochloride, clotrimazole,cloxacillin, demeclocycline, diclosxacillin, diiodohydroxyquin,doxycycline, ethambutol, ethambutol hydrochloride, erythromycin,erythromycin estolate, erythromycin stearate, farnesol, floxacillin,gentamicin, gentamicin sulfate, gramicidin, griseofulvin, haloprogin,haloquinol, hexachlorophene, iminocyldline, iodate, iodine,iodochlorhydroxyquin, kanamycin, kanamycin sulfate, lincomycin,lineomycin, lineomycin hydrochloride, macrolides, meclocycline,methacycline, methacycline hydrochloride, methenamine, methenaminehippurate, methenamine mandelate, methicillin, metronidazole,miconazole, miconazole hydrochloride, microcrystalline andnanocrystalline particles of silver, copper, zinc, mercury, tin, lead,bismuth, cadmium and chromium, minocycline, minocycline hydrochloride,mupirocin, nafcillin, neomycin, neomycin sulfate, netilmicin, netilmicinsulfate, nitrofurazone, norfloxacin, nystatin, octopirox, oleandomycin,orcephalosporins, oxacillin, oxytetracycline, oxytetracyclinehydrochloride, parachlorometa xylenol, paromomycin, paromomycin sulfate,penicillins, penicillin G, penicillin V, pentamidine, pentamidinehydrochloride, phenethicillin, polymyxins, quinolones, streptomycinsulfate, tetracycline, tobramycin, tolnaftate, triclosan, trifampin,rifamycin, rolitetracycline, spectinomycin, spiramycin, streptomycin,sulfonamide, tetracyclines, tetracycline, tobramycin, tobramycinsulfate, triclocarbon, triclosan, trimethoprim-sulfamethoxazole,tylosin, vancomycin, yrothricin and derivatives, esters, salts andmixtures thereof.

In an embodiment of the present invention, the active agent is anantidandruff agent. Suitable antidandruff agents include but are notlimited to aminexil, benzalkonium chloride, benzethonium chloride,3-bromo-1-chloro-5,5-dimethyl-hydantoin, chloramine B, chloramine T,chlorhexidine, N-chlorosuccinimide, climbazole-,1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethyl-hydantoin,betulinic acid, betulonic acid, celastrol, crataegolic acid, cromakalin,cyproterone acetate, dutasteride, finesteride, ibuprofen, ketoconozole,oleanolic acid, phenyloin, picrotone olamine, salicylic acid, seleniumsulphides, triclosan, triiodothyronine, ursolic acid, zinc gluconate,zinc omadine, zinc pyrithione and derivatives, esters, salts andmixtures thereof.

In an embodiment of the present invention, the active agent is anantihistamine. Suitable antihistamines include but are not limited tochlorcyclizine, diphenhydramine, mepyramine, methapyrilene,tripelennamine and derivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is anantimycotic Also termed antifungal agent. The terms “antimycotic” and“antifungal” as used herein include, but is not limited to, anysubstance being destructive to or inhibiting the growth of fungi andyeast or any substance having the capacity to inhibit the growth of orto destroy fungi and/or yeast.

In one or more embodiments, the antifungal agent is an agent that isuseful in the treatment of a superficial fungal infection of the skin,dermatophytosis, microsporum, trichophyton and epidermophytoninfections, candidiasis, oral candidiasis (thrush), candidiasis of theskin and genital mucous membrane, candida paronychia, which inflicts thenail and nail bed and genital and vaginal candida, which inflictgenitalia and the vagina.

Suitable antimycotics include but are not limited to allylamines,amorolfine, amphotericin B, azole compounds, bifonazole, butoconazole,chloroxine, clotrimazole, ciclopirox olamine, clotrimazole, econazole,elubiol, fenticonazole, fluconazole, flucytosine (5FC), griseofulvin,itraconazole, ketoconazole, mafenide acetate, miconazole, naftifine,natamycin, tolnaftate, nystatin, polyenes, oxiconazole, sulbentine,sulconazole, terbinafine, terconazole, tioconazole, undecylenic acid andderivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is anantipruritic. Suitable antipruritics include but are not limited tomenthol, methdilazine, trimeprazine, urea and derivatives, esters, saltsand mixtures thereof.

In an embodiment of the present invention, the active agent is anadditional antipsoriatic agent. Suitable additional antipsoriatic agentsinclude but are not limited to 6-aminonicotinamide, 6-aminonicotinicacid, 2-aminopyrazinamide, anthralin, 6-carbamoylnicotinamide,6-chloronicotinamide, 2-carbamoylpyrazinamide, corticosteroids,6-dimethylaminonicotinamide, dithranol, 6-formylaminonicotinamide,6-hydroxy nicotinic acid, 6-substituted nicotinamides, 6-substitutednicotinic acid, 2-substituted pyrazinamide, tazarotene,thionicotinamide, trichothecene mycotoxins and derivatives, esters,salts and mixtures thereof.

In an embodiment of the present invention, the active agent is anantirosacea agent. Suitable antirosacea agents include but are notlimited to azelaic acid, metronidazole, sulfacetamide and derivatives,esters, salts and mixtures thereof. Certain nonsteroidalanti-inflammatory agents, such as salicylic acid, salycilates, piroxicamand diclofenac are also useful for the treatment of Rosacea.

In an embodiment of the present invention, the active agent is anantiseborrheic agent. Suitable antiseborrheic agents include but are notlimited to glycolic acid, salicylic acid, selenium sulfide, zincpyrithione, a dicarboxylic acid, such as azelaic acid and derivatives,esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is anantiviral agent. Suitable antiviral agents include but are not limitedto acyclovir, gancyclovir, ribavirin, amantadine, rimantadinenucleoside-analog reverse transcriptase inhibitors, such as zidovudine,didanosine, zalcitabine, tavudine, lamivudine and vidarabine,non-nucleoside reverse transcriptase inhibitors, such as nevirapine anddelavirdine, protease inhibitors, such as saquinavir, ritonavir,indinavir and nelfinavir, and interferons and derivatives, esters, saltsand mixtures thereof.

In an embodiment of the present invention, the active agent is achemotherapeutic agent. Suitable chemotherapeutic agents include but arenot limited to daunorubicin, doxorubicin, idarubicin, amrubicin,pirarubicin, epirubicin, mitoxantrone, etoposide, teniposide,vinblastine, vincristine, mitomycin C, 5-FU, paclitaxel, docetaxel,actinomycin D, colchicine, topotecan, irinotecan, gemcitabinecyclosporin, verapamil, valspodor, probenecid, MK571, GF120918,LY335979, biricodar, terfenadine, quinidine, pervilleine A, XR9576 andderivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is acorticosteroid. Suitable corticosteroids include but are not limited toalclometasone dipropionate, amcinafel, amcinafide, amcinonide,beclomethasone, beclomethasone dipropionate, betamethsone, betamethasonebenzoate, betamethasone dexamethasone-phosphate, dipropionate,betamethasone valerate, budesonide, chloroprednisone, chlorprednisoneacetate, clescinolone, clobetasol, clobetasol propionate, clobetasolvalerate, clobetasone, clobetasone butyrate, clocortelone, cortisone,cortodoxone, craposone butyrate, desonide, desoxymethasone,dexamethasone, desoxycorticosterone acetate, dichlorisone, diflorasonediacetate, diflucortolone valerate, difluorosone diacetate,diflurprednate, fluadrenolone, flucetonide, flucloronide, flucloroloneacetonide, flucortine butylesters, fludroxycortide, fludrocortisone,flumethasone, flumethasone pivalate, flumethasone pivalate, flunisolide,fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl,fluocortolone, fluorometholone, fluosinolone acetonide, fluperolone,fluprednidene acetate, fluprednisolone hydrocortamate, fluradrenolone,fluradrenolone acetonide, flurandrenolone, fluticasone, halcinonide,halobetasol, hydrocortisone, hydrocortisone acetate, hydrocortisonebutyrate, hydrocortisone cyclopentylpropionate, hydrocortisone valerate,hydroxyltriamcinolone, medrysone, meprednisone, .alpha.-methyldexamethasone, methylprednisolone, methylprednisolone acetate,mometasone furoate, paramethasone, prednisolone, prednisone,pregnenolone, progesterone, spironolactone, triamcinolone, triamcinoloneacetonide and derivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is a hairgrowth regulator. Suitable hair growth regulators include but are notlimited to N-acetylgalactosamine, N-acetylglucosamine,N-acetylmannosamine, acitretin, aminexil, ascomycin, asiatic acid,azelaic acid, benzalkonium chloride, benzethonium chloride, benzydamine,benzyl nicotinate, benzoyl peroxide, benzyl peroxide, betulinic acid,betulonic acid, calcium pantothenate, celastrol, cepharanthine,chlorpheniramine maleate, clinacycin hydrochloride, crataegolic acid,cromakalin, cyproterone acetate, diazoxide, diphenhydraminehydrochloride, dutasteride, estradiol, ethyl-2-hydroxypropanoate,finasteride, D-fucono-1,5-lactone, furoate, L-galactono-1,4-lactone,D-galactosamine, D-glucaro-1,4-lactone, D-glucosamine-3-sulphate,hinokitiol, hydrocortisone, 2-hydroxypropionic acid, isotretinoin,itraconazole, ketoconazole, latanoprost, 2-methyl propan-2-ol,minocyclin, minoxidil, mipirocin, mometasone, oleanolic acid, panthenol,1,10-phenanthroline, phenyloin, prednisolone, progesterone, propan-2-ol,pseudoterins, resorcinol, selenium sulfide, tazarotene, triclocarbon,triclosan, triiodothyronine, ursolic acid, zinc pyrithione andderivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is ahormone. Suitable hormones include but are not limited tomethyltestosterone, androsterone, androsterone acetate, androsteronepropionate, androsterone benzoate, androsteronediol,androsteronediol-3-acetate, androsteronediol-17-acetate,androsteronediol 3-17-diacetate, androsteronediol-17-benzoate,androsteronedione, androstenedione, androstenediol,dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate,dromostanolone, dromostanolone propionate, ethylestrenol,fluoxymesterone, nandrolone phenpropionate, nandrolone decanoate,nandrolone furylpropionate, nandrolone cyclohexane-propionate,nandrolone benzoate, nandrolone cyclohexanecarboxylate,androsteronediol-3-acetate-1-7-benzoate, oxandrolone, oxymetholone,stanozolol, testosterone, testosterone decanoate, 4-dihydrotestosterone,5a-dihydrotestosterone, testolactone, 17a-methyl-19-nortestosterone,desogestrel, dydrogesterone, ethynodiol diacetate, medroxyprogesterone,levonorgestrel, medroxyprogesterone acetate, hydroxyprogesteronecaproate, norethindrone, norethindrone acetate, norethynodrel,allylestrenol, 19-nortestosterone, lynoestrenol, quingestanol acetate,medrogestone, norgestrienone, dimethisterone, ethisterone, cyproteroneacetate, chlormadinone acetate, megestrol acetate, norgestimate,norgestrel, desogrestrel, trimegestone, gestodene, nomegestrol acetate,progesterone, 5a-pregnan-3b,20a-diol sulfate, 5a-pregnan-3b,20b-diolsulfate, 5a-pregnan-3b-ol-20-one, 16,5a-pregnen-3b-ol-20-one,4-pregnen-20b-ol-3-one-20-sulfate, acetoxypregnenolone, anagestoneacetate, cyproterone, dihydrogesterone, fluorogestone acetate,gestadene, hydroxyprogesterone acetate, hydroxymethylprogesterone,hydroxymethyl progesterone acetate, 3-ketodesogestrel, megestrol,melengestrol acetate, norethisterone, progestins and derivatives,esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is ahydroxyacid. Suitable hydroxy acids include but are not limited toagaricic acid, aleuritic acid, allaric acid, altraric acid, arabiraricacid, ascorbic acid, atrolactic acid, benzilic acid, citramalic acid,citric acid, dihydroxytartaric acid, erythraric acid, galactaric acid,galacturonic acid, glucaric acid, glucuronic acid, glyceric acid,glycolic acid, gularic acid, gulonic acid, hydroxypyruvic acid, idaricacid, isocitric acid, lactic acid, lyxaric acid, malic acid, mandelicacid, mannaric acid, methyllacetic acid, mucic acid, phenyllacetic acid,pyruvic acid, quinic acid, ribaric acid, ribonic acid, saccharic acid,talaric acid, tartaric acid, tartronic acid, threaric acid, tropic acid,uronic acids, xylaric acid and derivatives, esters, salts and mixturesthereof.

In an embodiment of the present invention, the active agent is akeratolytic agent. The term “keratolytic agent” is used herein to mean acompound which loosens and removes the stratum corneum of the skin, oralters the structure of the keratin layers of skin. Keratolytic agentsare used in the treatment of many dermatological disorders, whichinvolve dry skin, hyperkeratiinization (such as prsoriasis), skinitching (such as xerosis), acne and rosacea. Suitable keratolytic agentsinclude but are not limited to N-acetylcysteine, azelaic acid, cresols,dihydroxy benzene compounds, such as resorcinol and hydroquinone,alpha-hydroxy acids, such as lactic acid and glycolic acid, phenol,pyruvic acid, resorcinol, sulfur, salicylic acid, retinoic acid,isoretinoic acid, retinol, retinal, urea and derivatives, esters, saltsand mixtures thereof.

In an embodiment of the present invention, the active agent is a lactam.Suitable lactams include but are not limited to L-galactono-1,4-lactam,L-arabino-1,5-lactam, D-fucono-1,5-lactam, D-glucaro-1,4-lactam,D-glucurono-6,3-lactam, 2,5-tri-O-acetyl-D-glucurono-6,3-lactam,2-acetamido-2-deoxyglucono-1,5-1-actam,2-acetamido-2-deoxygalactono-1,5-lactam, D-glucaro-1,4:6,3-dilactam-,L-idaro-1,5-lactam, 2,3,5,tri-O-acetyl-D-glucaro-1,4-lactam,2,5-di-O-acetyl-D-glucaro-1,4:6,3-dilactam, D-glucaro-1,5-lactam methylester, 2-propionoamide-2-deoxyglucaro-1,5-lactam and derivatives,esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is anon-steroidal anti-inflammatory agent. Suitable non-steroidalanti-inflammatory agent include but are not limited to azelaic acid,oxicams, piroxicam, isoxicam, tenoxicam, sudoxicam, CP-14,304,salicylates, aspirin, disalcid, benorylate, trilisate, safapryn,solprin, diflunisal, fendosal, acetic acid derivatives, diclofenac,fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac,tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac,oxepinac, felbinac, ketorolac, fenamates, mefenamic, meclofenamic,flufenamic, niflumic, tolfenamic acids, propionic acid derivatives,ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen,fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen,miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofen, pyrazoles,phenylbutazone, oxyphenbutazone, feprazone, azapropazone, trimethazoneand derivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent isinsecticide. The term “insecticide, is used herein to mean a compoundwhich kills, inhibits the growth of, impeded the proliferation of orrepels insects. Insecticides include, for example, agents that can killlice, flees, ticks, mites, scabies and mousquitos, as well as agentsthat repel such insects. Suitable insecticides include but are notlimited to DDT, lindane, malathion, permethrin, allethrin,biopermethrin, transpermethrin, phenothrin, diethyl-m-toluamide,dimethyl phthalate, piperonyl butoxide, pyrethroids and derivatives,esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is avasodilator. Suitable vasodilators include but are not limited to agentsthat modulate the activity of the enzyme nitric oxide synthase,nicotinic acid, ethyl nicotinate, amyl nitrite, amyl nitrate, ethylnitrite, butyl nitrite, isobutyl nitrite, glyceryl trinitrate, octylnitrite, sodium nitrite, sodium nitroprusside, clonitrate, erythrityltetranitrate, isosorbide mononitrate, isosorbide dinitrate, mannitolhexanitrate, pentaerythritol tetranitrate, penetrinitol, triethanolaminetrinitrate, troInitrate phosphate (triethanolamine trinitratediphosphate), propatylnitrate, nitrite esters of sugars, nitrite estersof polyols, nitrate esters of sugars, nitrate esters of polyols,nicorandil, apresoline, diazoxide, hydralazine, hydrochlorothiazide,minoxidil, pentaerythritol, tolazoline, scoparone, a beta-adrenergicblocker, an alpha-adrenoceptor blocker, a prostaglandin, sildenafil,dipyridamole, catecholamine, isoproternol, furosemide, prostaglandin,prostacyclin, enalaprilat, morphine, acepromazine, prazosin (α-blocker),enalapril, Captopril, amlodipine, minoxidil, tadalafil, vardenafil,phenylephrin, etilefein, caffeine, capsaicin, an extract capsicum,achillea millefolium (Yarrow), allium sativum (garlic), amoraciarusticana (horseradish), berberis vulgaris (barberry), cimicifugaracemosa (black cohosh), coleus forskholii (coleus), coptis(goldenthread), crataegus (hawthorn), eleutherococcus senticosus(siberian ginseng), ginkgo biloba (ginkgo), melissa offiicnalis (lemonbalm), olea europaea (olive leaf), panax ginseng (Chinese ginseng),petroselinum crispum (parsley), scutellaria baicalensis (baicalskullcap), tilia europaea (linden flower), trigonella foenum-graecum(fenugreek), urtica dioica (nettles), valeriana officinalis (valerian),viburnum (cramp, bark, black haw), veratrum viride (American hellebore),verbena officinalis (vervain), xanthoxylum americanum (prickly ash),zing iber officinale (ginger), rauwolfia serpentina (Indian snakeroot),viscum album, wild yam, sasparilla, licorice, damiana, yucca, sawpalmetto, gotu kola (centella asiatica), yohimbine and salts, hazel nut,brazil nut and walnut, and derivatives, esters, salts and mixturesthereof.

In an embodiment of the present invention, the active agent is avasoconstrictor. Suitable vasodilators include but are not limited toephedrine, epinephrine, phenylephrine, angiotensin, vasopressin; anextract ephedra sinica (ma huang), polygonum bistorta (bistort root),hamamelis virginiana (witch hazel), hydrastis canadensis (goldenseal),lycopus virginicus (bugleweed), aspidosperma quebracho (quebrachoblanco), cytisus scoparius (scotch broom) and cypressand andderivatives, esters, salts and mixtures thereof.

In an embodiment of the present invention, the active agent is aretinoid. Suitable retinoids include but are not limited to retinol,retinal, retinoic acid, all-trans retinoic acid, isotretinoin,tazarotene, adapalene, 13-cis-retinoic acid, acitretin all-trans betacarotene, alpha carotene, lycopene, 9-cis-beta-carotene, lutein andzeaxanthin.

In an embodiment of the present invention, the active agent is a vitaminD analog. Suitable retinoids include but are not limited tocalcipotriene, cholecalciferol, 25-hydroxycholecalciferol,1α,25-dihydroxycholecalciferol, ergocalciferol,1α,25-dihydroxyergocalciferol, 22,23-dihydroergocalciferol,1,24,25-trihydroxycholecalciferol, previtamin D₃, tachysterol₃ (alsotermed tacalciol), isovitamin D₃, dihydrotachysterol₃,(1S)-hydroxycalciol, (24R)-hydroxycalcidiol, 25-fluorocalciol,ercalcidiol, ertacalciol, (5E)-isocalciol, 22,23-dihydroercalciol,(24S)-methylcalciol, (5E)-(10S)-10,19-dihydroercalciol,(24S)-ethylcalciol and (22E)-(24R)-ethyl-22,23-didehydrocalciol. In apreferred embodiment, the vitamin D analog is calcipotriene, which isuseful in the treatment of psoriasis.

In an embodiment of the present invention, the active agent is selectedfrom the group consisting of an immunosuppressants and immunoregulatingagents. Suitable immunosuppressants and immunoregulating agents includebut are not limited to cyclic peptides, such as cyclosporine,tacrolimus, tresperimus, pimecrolimus, sirolimus (rapamycin), verolimus,laflunimus, laquinimod, imiquimod derivatives, esters, salts andmixtures thereof. In one or more embodiments, the immunomodulator is acalcineurin Inhibitor.

In an embodiment of the present invention, the active agent is a wartremover. Suitable wart removers include but are not limited toimiquimod, podophyllotoxin and derivatives, esters, salts and mixturesthereof.

In an embodiment of the present invention, the active agent is aphotodynamic therapy (PDT) agent. Suitable PDT agents include but arenot limited to modified porphyrins, chlorins, bacteriochlorins,phthalocyanines, naphthalocyanines, pheophorbides, purpurins, m-THPC,mono-L-aspartyl chlorin e6, bacteriochlorins, phthalocyanines,benzoporphyrin derivatives, as well as photosensitiser precursors, suchas aminolevulinic acid and derivatives, esters, salts and mixturesthereof.

In an embodiment of the present invention, the active agent is anantioxidant or a radical scavenger. Suitable antioxidants and radicalscavengers agents include but are not limited to ascorbic acid, ascorbylesters of fatty acids, magnesium ascorbyl phosphate, sodium ascorbylphosphate, ascorbyl sorbate, tocopherol, tocopheryl sorbate, tocopherylacetate, butylated hydroxy benzoic acid,6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, gallic acid,propyl gallate, uric acid, sorbic acid, lipoic acid,diethylhydroxylamine, amino-guanidine, glutathione, dihydroxy fumaricacid, lycine pidolate, arginine pilolate, nordihydroguaiaretic acid,bioflavonoids, curcumin, lysine, methionine, proline, superoxidedismutase, silymarin, tea extracts, grape skin/seed extracts, melanin,and polyunsaturated oils, containing omega-3 and omega-6 fatty acids(e.g., linoleic and linolenic acid, gamma-linoleic acid,eicosapentaenoic acid and docosahexaenoic acid and derivatives, esters,salts and mixtures thereof.

In an embodiment of the present invention, the active agent is aself-tanning agent, such as dihydroxyacetone.

In an embodiment of the present invention, the active agent is an agent,capable of treating hyperhidrosis. Suitable hyperhidrosis agents includebut are not limited to anticholinergic drugs, boric acid, tannic acid,resorcinol, potassium permanganate, formaldehyde, glutaraldehyde,methenamine, a Lewis acid, aluminum chloride, aluminum chlorohydrates,zirconium chlorohydrates, aluminum-zirconium-Glycine (AZG) complex,aluminum hydroxybromide, a glycopyrrolate compound, a 5-alpha-reductaseinhibitor, finasteride, epristeride, flutamide, spironolactone, sawpalmetto extract, cholestan-3-one, a mono- and dicarboxylic acid having4 to 18 carbon atoms, botulinum toxin, a 5-HT2C receptor antagonist, a5-HT2C receptor antagonist, ketanserin, ritanserin, mianserin,mesulergine, cyproheptadine, fluoxetine, mirtazapine, olanzapine andziprasidone.

In an embodiment of the present invention, the active agent is asunscreen agent. Suitable sunscreen agents include but are not limitedto titanium dioxide, zinc oxide, zirconium oxide, iron oxide,p-aminobenzoic acid and its derivatives (ethyl, isobutyl, glycerylesters; p-dimethylaminobenzoic acid); anthranilic acid derivatives(i.e., o-amino-benzoates, methyl, menthyl, phenyl, benzyl, phenylethyl,linalyl, terpinyl, and cyclohexenyl esters); salicylates (amyl, phenyl,octyl, benzyl, menthyl, glyceryl, and di-pro-pyleneglycol esters);cinnamic acid derivatives (menthyl and benzyl esters, a-phenylcinnamonitrile; butyl cinnamoyl pyruvate); dihydroxycinnamic acidderivatives (umbelliferone, methylumbelliferone,methylaceto-umbelliferone); trihydroxy-cinnamic acid derivatives(esculetin, methylesculetin, daphnetin, and the glucosides, esculin anddaphnin); hydrocarbons (diphenylbutadiene, stilbene); dibenzalacetoneand benzalacetophenone; naphtholsulfonates (sodium salts of2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic acids);di-hydroxynaphthoic acid, o- and p-hydroxybiphenyldisulfonates, coumarinderivatives (7-hydroxy, 7-methyl, 3-phenyl), diazoles(2-acetyl-3-bromoindazole, phenyl benzoxazole, methyl naphthoxazole,quinine salts (bisulfate, sulfate, chloride, oleate, and tannate);quinoline derivatives (8-hydroxyquinoline salts, 2-phenylquinoline);hydroxy- or methoxy-substituted benzophenones; uric and violuric acids;tannic acid and its derivatives (e.g., hexaethylether); (butyl carbotol)(6-propyl piperonyl)ether; hydroquinone; benzophenones (oxybenzene,sulisobenzone, dioxybenzone, benzoresorcinol,2,2′,4,4′-tetrahydroxybenzophenone,2,2′-dihydroxy-4,4′-dimethoxybenzophenone, octabenzone;4-isopropyldibenzoylmethane; butylmethoxydibenzoylmethane; etocrylene;octocrylene; [3-(4′-methylbenzylidene bornan-2-one), terephthalylidenedicamphor sulfonic acid and 4-isopropyl-di-benzoylmethane.

In an embodiment of the present invention, the active agent is afigure-forming agent and an agent, capable of treating cellulite.Suitable such agents include but are not limited to baldderwack extract,butcher's, broom, cayenne, dandelion, red clover, ginkgo biloba, horsechestnut, witch hazel and borage oil, caffeic acid, nicotinic acid,theophiline and pentoxyphilline and salts and derivatives thereof.

Several disorders of the skin, body cavity or mucosal surface (e.g., themucosa or the cavity of the nose, mouth, eye, ear, vagina or rectum)involve a combination of etiological factors. For example, fungal andbacterial infections and that are inflamed and have symptoms of rednessand/or itching warrant therapy that combines an anti-infective agent andan anti-inflammatory agent. Thus, in several cases, combining at leasttwo active agents that treat different etiological factors results in asynergistic effect and consequently higher success rate of thetreatment.

In certain cases, the composition contains two active agents, where eachof the active agents require a different pH environment in order toremain stable. For example, corticosteroids are typically stable atacidic pH values (they have a maximum stability at a pH of about 4-6)and of vitamin D analogues are typically stable at basic pH values (theyhave a maximum stability at pH values above about 8). In order tocircumvent the problem of instability it is preferred that thecomposition is substantially non-aqueous or preferably waterless. Theterm “substantially non-aqueous” is intended to indicate that thecomposition has a water content below about 5%, preferably below about2%, such as below about 1.5%. The formulation can then be modulated by amodulating agent addative that provides, for example, an artificial pHcloser to the more sensitive of the two sensitive actives oralternatively closer to the more pH sensitive of the two actives. On apragmatic level formulating the composition with an artificial pH closeto that of skin may be an advantage.

In one or more embodiments the active pharmaceutical or cosmetic agentis an agent which is sensitive to pH such that it is more stable at acertain pH or pH range and tends to react or break down or isomerise ata different pH or pH range. In a preferred embodiment the active agentincludes the following non limiting examples: steroids (most are stableat acidic ph of about 4.5); antibiotics, such as tetracycline's whichare stable at acidic ph (e.g. oxytetracycline, clindamycin,);penicillinic and cephalosporinic antibiotics, (such as, ampicillin,benzylpenicillin, carbenicillin, cephydroxil, cefotaxime, cephalotin,and cephradine); triamcinolone; nystatin (stable at about ph 7.0);sulfacetamide; and amphotericin; vitamins are generally ph sensitive andexamples are ascorbic acid which is stable in slightly acidic conditionsand vitamin D analogues that are stable at basic pH, and nicotine amide;NSAID's such as aspirin and indomethacin; atropine; piloarpine; procaineamide; aztrenam; barbiturates; captopril nucletide derivatives such ascytarabineepinephrine; parabens such as ethylparaben methlparaben;anticancer agents such as fluorouracil and iodoxuridine; morphineanalgesic; prostaglandins and thiamine HCl.

Fields of Applications

The foamable carrier of the present invention is suitable for treatingany infected surface. In one or more embodiments, foamable carrier issuitable for administration to the skin, a body surface, a body cavityor mucosal surface, e.g., the cavity and/or the mucosa of the nose,mouth, eye, ear, respiratory system, vagina or rectum (severally andinterchangeably termed herein “target site”).

By selecting a suitable active agent, or a combination of at least twoactive agents, the foamable composition of the present invention isuseful in treating an animal or a human patient having any one of avariety of dermatological disorders, including dermatological pain,dermatological inflammation, acne, acne vulgaris, inflammatory acne,non-inflammatory acne, acne fulminans, nodular papulopustular acne, acneconglobata, dermatitis, bacterial skin infections, fungal skininfections, viral skin infections, parasitic skin infections, skinneoplasia, skin neoplasms, pruritis, cellulitis, acute lymphangitis,lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneousinfections, scalded skin syndrome, folliculitis, furuncles, hidradenitissuppurativa, carbuncles, paronychial infections, rashes, erythrasma,impetigo, eethyma, yeast skin infections, warts, molluscum contagiosum,trauma or injury to the skin, post-operative or post-surgical skinconditions, scabies, pediculosis, creeping eruption, eczemas, psoriasis,pityriasis rosea, lichen planus, pityriasis rubra pilaris, edematous,erythema multiforme, erythema nodosum, grannuloma annulare, epidermalnecrolysis, sunburn, photosensitivity, pemphigus, bullous pemphigoid,dermatitis herpetiformis, keratosis pilaris, callouses, corns,ichthyosis, skin ulcers, ischemic necrosis, miliaria, hyperhidrosis,moles, Kaposi's sarcoma, melanoma, malignant melanoma, basal cellcarcinoma, squamous cell carcinoma, poison ivy, poison oak, contactdermatitis, atopic dermatitis, rosacea, purpura, moniliasis,candidiasis, baldness, alopecia, Behcet's syndrome, cholesteatoma,Dercum disease, ectodermal dysplasia, gustatory sweating, nail patellasyndrome, lupus, hives, hair loss, Hailey-Hailey disease, chemical orthermal skin burns, scleroderma, aging skin, wrinkles, sun spots,necrotizing fasciitis, necrotizing myositis, gangrene, scarring, andvitiligo.

Likewise, the foamable composition of the present invention is suitablefor treating a disorder of a body cavity or mucosal surface, e.g., themucosa of the nose, mouth, eye, ear, respiratory system, vagina orrectum. Non limiting examples of such conditions include chlamydiainfection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, humanpapillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis,chancroid, granuloma Inguinale, lymphogranloma venereum, mucopurulentcervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU),trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeastinfection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN),contact dermatitis, pelvic inflammation, endometritis, salpingitis,oophoritis, genital cancer, cancer of the cervix, cancer of the vulva,cancer of the vagina, vaginal dryness, dyspareunia, anal and rectaldisease, anal abscess/fistula, anal cancer, anal fissure, anal warts,Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecalincontinence, constipation, polyps of the colon and rectum.

In an embodiment of the present invention, the composition is useful forthe treatment of an infection. In one or more embodiments, thecomposition is suitable for the treatment of an infection, selected fromthe group of a bacterial infection, a fungal infection, a yeastinfection, a viral infection and a parasitic infection.

In an embodiment of the present invention, the composition is useful forthe treatment of wound, ulcer and burn. This use is particularlyimportant since the composition of the present invention creates a thin,semi-occlusive layer, which coats the damaged tissue, while allowingexudates to be released from the tissue.

The composition of the present invention is also suitable foradministering a hormone to the skin or to a mucosal membrane or to abody cavity, in order to deliver the hormone into the tissue of thetarget organ, in any disorder that responds to treatment with a hormone.

In light of the hygroscopic nature of the water-free composition, it isfurther suitable for the treatment and prevention of post-surgicaladhesions. Adhesions are scars that form abnormal connections betweentissue surfaces. Post-surgical adhesion formation is a naturalconsequence of surgery, resulting when tissue repairs itself followingincision, cauterization, suturing, or other means of trauma. Whencomprising appropriate protective agents, the foam is suitable for thetreatment or prevention of post surgical adhesions. The use of foam isparticularly advantageous because foam can expand in the body cavity andpenetrate into hidden areas that cannot be reached by any otheralternative means of administration.

Substantially Alcohol-Free

According to one or more embodiments, the foamable composition issubstantially alcohol-free, i.e., free of short chain alcohols. Shortchain alcohols, having up to 5 carbon atoms in their carbon chainskeleton and one hydroxyl group, such as ethanol, propanol, isopropanol,butaneol, iso-butaneol, t-butaneol and pentanol, are considered lessdesirable solvents or polar solvents due to their skin-irritatingeffect. Thus, the composition is substantially alcohol-free and includesless than about 5% final concentration of lower alcohols, preferablyless than about 2%, more preferably less than about 1%.

Shakability

‘Shakability’ means that the composition contains some or sufficientflow to allow the composition to be mixed or remixed on shaking. Thatis, it has fluid or semi fluid properties. In some very limited cases itmay still be possible to have a foamable composition which is flowablebut not apparently shakable.

Breakability

A breakable foam is thermally stable or substantially so, yet breaksunder sheer force. The breakable foam of the present invention is not“quick breaking”, i.e., it does not readily collapse upon exposure tobody temperature environment. Sheer-force breakability of the foam isclearly advantageous over thermally induced breakability, (due to, forexample, the presence of alcohol) since it allows comfortableapplication and well directed administration to the target area.

Chemical Instability and Stability

By chemical instability of one or more active agents is meant that atleast one of the one or more active agents is susceptible to one or moreof inter alia reaction, breakdown, ionization or oxidation or the ratethereof is increased when incorporated into a pharmaceutical or cosmeticcarrier that is non aqueous or substantially non aqueous and notcomprising a modulating agent.

Conversely by chemical stability of one or more active agents is meantthat at least one of the one or more active agents is less susceptibleto one or more of inter alia reaction, breakdown, ionization oroxidation or the rate thereof is impeded when incorporated into apharmaceutical or cosmetic carrier that is non aqueous or substantiallynon aqueous and comprising a modulating agent.

Other foamable compositions are described in: U.S. Publication No.05-0232869, published on Oct. 20, 2005, entitled NONSTEROIDALIMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. PublicationNo. 05-0205086, published on Sep. 22, 2005, entitled RETINOIDIMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. PublicationNo. 06-0018937, published on Jan. 26, 2006, entitled STEROID KIT ANDFOAMABLE COMPOSITION AND USES THEREOF; U.S. Publication No. 05-0271596,published on Dec. 8, 2005, entitled VASOACTIVE KIT AND COMPOSITION ANDUSES THEREOF; U.S. Publication No. 06-0269485, published on Nov. 30,2006, entitled ANTIBIOTIC KIT AND COMPOSITION AND USES THEREOF; U.S.Publication No. 07-0020304, published on Jan. 25, 2007, entitledNON-FLAMMABLE INSECTICIDE COMPOSITION AND USES THEREOF; U.S. PublicationNo. 06-0193789, published on Aug. 31, 2006, entitled FILM FORMINGFOAMABLE COMPOSITION; U.S. patent application Ser. No. 11/732,547, filedon Apr. 4, 2007, entitled ANTI-INFECTION AUGMENTATION OF FOAMABLECOMPOSITIONS AND KIT AND USES THEREOF; U.S. Provisional PatentApplication No. 60/789,186, filed on Apr. 4, 2006, KERATOLYTICANTIFUNGAL FOAM; U.S. Provisional Patent Application No. 0/815948, filedon Jun. 23, 2006, entitled FOAMABLE COMPOSITIONS COMPRISING A CALCIUMCHANNEL BLOCKER, A CHOLINERGIC AGENT AND A NITRIC OXIDE DONOR; U.S.Provisional Patent Application No. 60/818,634, filed on Jul. 5, 2006,entitled DICARBOXYLIC ACID FOAMABLE VEHICLE AND PHARMACEUTICALCOMPOSITIONS THEREOF; U.S. Provisional Patent Application No.60/843,140, filed on Sep. 8, 2006, entitled FOAMABLE VEHICLE AND VITAMINPHARMACEUTICAL COMPOSITIONS THEREOF, all of which are incorporatedherein by reference in their entirety. More particularly any of theactive ingredients; the solvents; the surfactants; foam adjuvants;polymeric agents, penetration enhancers; preservatives, humectants;moisturizers; and other excipients as well as the propellants listedtherein can be applied herein and are incorporated by reference.

The invention is described with reference to the following examples.This invention is not limited to these examples and experiments. Manyvariations will suggest themselves and are within the full intendedscope of the appended claims.

Methodology

The formulas of the present invention may be made in the followinggeneral way with appropriate adjustments for each formulation as will beappreciated by someone skilled in the art. Polymers, if any, are mixed,swelled and solubilized in the waterless medium, when necessary, withappropriate heat until it forms a clear solution. Stabilizingsurfactants added usually with heat, until a homogeneous mixture isobtained, the mixture is then allowed to cool. The remainder of theingredients, are then added with mixing until they have dissolved in themedium. The active agent is usually added at the end once the modulatingagent has been incorporated. For foam the canisters are then filled withthe above waterless formula, sealed and crimped with a valve andpressurized with the propellant.

A general procedure for preparing foamable compositions is set out in WO2004/037225, which is incorporated herein by reference.

Waterless Foam

-   -   1. Dissolve the polymers, if any, in the main solvent with        heating or cooling as appropriate for specific polymer. Add the        all other ingredients and heat to 75° C. to melt and dissolve        the various ingredients.    -   2. Cool to below 40° C. and add sensitive ingredients with mild        mixing.    -   3. Cool to room temperature.    -   Note that for substantially waterless foam a small amount of        water is added before step 2.

Oily Waterless Foam

-   -   1. Mix all ingredients excluding polymers and heat to 75° C. to        melt and dissolve and obtain homogeneous mixture.    -   2. Mix well and cool to below 40° C. and add the polymers, if        any, and sensitive ingredients with moderate mixing.    -   3. Cool to room temperature.    -   Note that for substantially waterless foam a small amount of        water is added before step 2.        Oily Foam with Phospholipids    -   1. Swell the phospholipids in the main oily solvent under mixing        for at least 20 minutes until uniform suspension is obtained.    -   2. Add all other ingredients excluding polymers and heat to        75° C. to melt and dissolve and obtain homogeneous mixture.    -   3. Mix well and cool to below 40° C. and add the polymers, if        any, and sensitive ingredients with moderate mixing.    -   4. Cool to room temperature.    -   5. In case of polymers dissolved or organic solvent, dissolve        the polymers in the solvent with heating or cooling as        appropriate for specific polymer and add to the oily mixture        under vigorous mixing at ˜40° C.    -   Note that for substantially waterless foam a small amount of        water is added step 5.

Production Under Vacuum

Optionally, the foamable formulation may be produced under nitrogen andunder vacuum. Whilst the whole process can be carried out under anoxygen free environment, it can be sufficient to apply a vacuum afterheating and mixing all the ingredients to obtain an emulsion orhomogenous liquid. Preferrably the production chamber is equipped toapply a vacuum but if not the formulation can be for example placed in adessicator to remove oxygen prior to filing and crimping.

Canisters Filling and Crimping

Each aerosol canister is filled with PFF and crimped with valve usingvacuum crimping machine. The process of applying a vacuum will causemost of the oxygen present to be eliminated. Addition of hydrocarbonpropellant may without being bound by any theory further help to reducethe likelihood of any remaining oxygen reacting with the activeingredient. It may do so, without being bound by any theory, by one ormore of dissolving in the oil or hydrophobic phase of the formulation,by dissolving to a very limited extent in the aqueous phase, bycompeting with some oxygen from the formulation, by diluting out anyoxygen, by a tendency of oxygen to occupy the dead space, and by oxygenoccupying part of the space created by the vacuum being the unfilledvolume of the canister or that remaining oxygen is renderedsubstantially ineffective in the formulation.

Pressurizing

Propellant Filling

Pressurizing is carried out using a hydrocarbon gas or gas mixture.Canisters are filled and then warmed for 30 sec in a warm bath at 50° C.and well shaken immediately thereafter.

Closure Integrity Test.

Each pressurized canister is subjected to bubble and crimping integritytesting by immersing the canister in a 60° C. water bath for 2 minutes.Canisters are observed for leakage as determined by the generation ofbubbles. Canisters releasing bubbles are rejected.

Tests

By way of non limiting example the objectives of hardness, collapse timeand FTC stability tests are briefly set out below as would beappreciated by a person of the art.

Hardness

LFRA100 instrument is used to characterize hardness. A probe is insertedinto the test material. The resistance of the material to compression ismeasured by a calibrated load cell and reported in units of grams on thetexture analyzer instrument display. Preferably at least three repeattests are made. The textural characteristics of a dispensed foam canaffect the degree of dermal penetration, efficacy, spreadability andacceptability to the user. The results can also be looked at as anindicator of softness. Note: the foam sample is dispensed into analuminum sample holder and filled to the top of the holder.

Collapse Time

Collapse time (CT) is examined by dispensing a given quantity of foamand photographing sequentially its appearance with time duringincubation at 36° C. It is useful for evaluating foam products, whichmaintain structural stability at skin temperature for at least 1 min.

Viscosity

Viscosity is measured with Brookfield LVDV-II+PRO with spindle SC4-25 atambient temperature and 10, 5 and 1 RPM. Viscosity is usually measuredat 10 RPM. However, at about the apparent upper limit for the spindle of˜>50,000CP, the viscosity at 1 RPM may be measured, although the figuresare of a higher magnitude.

Conductance

The conductance meter is calibrated. The electrode is inserted into asuficient volume of composition and the conductance reading is recorded.Mesurements with foamable compositions are made prior to addition ofpropellant.

FTC (Freeze Thaw Cycles)

To check the foam appearance under extreme conditions of repeated cyclesof cooling, heating, (first cycle) cooling, heating (second cycle) etc.,commencing with −100° C. (24 hours) followed by +400° C. (24 hours)measuring the appearance and again repeating the cycle for up to threetimes.

Focus Group

Five healthy volunteers selected at random were give a sample of foamformulation and applied it to the skin on their forearm and were askedto complete a questionnaire.

Chemical Stability

The amount of active agent present is analysed in foam expelled fromvarious pressurized canisters containing foam formulations using HPLC.Analysis is carried out at zero time and at appropriate time intervalsthereafter. The canisters are stored in controlled temperatureincubators at 5 C, at 25 C, at, 40 C and at 50 C. At appropriate timeintervals canisters are removed and the amount of active agent in thefoam sample is measured.

Analysis

About 1 g of foam or pre-foam formulation is dissolved in 0.1% aceticacid in methanol (diluent), to which internal standard (1S) solution isadded. BMV, BMV-21 and are extracted by heating, cooling andcentrifugation of the sample solution. The clear layer is analyzed byHPLC using a C-18 column; elution is performed with a mobile phasecontaining acetonitrile:water 55:45. The content of BMV and BMV-21 iscalculated using the respective peak area ratio against average peakarea ratio of BMV standard (0.2 mg/mL) to the IS present in the standardsolution at the same concentration as in samples. The details of themethod conditions are as follows: the column type is Acquity BEH C-18,1.7 μm, 50×2.1 mm in 40° C., the flow is 0.5 mL/min, the detector: UV,at 254 nm injection volume is 4 μL.; the diluents is 0.1% acetic acid inwater:acetonitrile, 45:55 (v/v) and the mobile phase content iswater:acetonitrile, 45:55 (v/v). The run time is 4 min. The method canbe carried out by HPLC using a different but appropriate column of thesame type.

Bubble Size

Foams are made of gas bubbles entrapped in liquid. The bubble size anddistribution reflects in the visual texture and smoothness of the foam.Foam bubbles size is determined by dispensing a foam sample on a glassslide, taking a picture of the foam surface with a digital cameraequipped with a macro lens. The diameter of about 30 bubbles is measuredmanually relatively to calibration standard template. Statisticalparameters such as mean bubble diameter, standard deviation andquartiles are then determined. Measuring diameter may also be undertakenwith image analysis software. The camera used was a Nikon D40X Camera(resolution 10MP) equipped with Sigma Macro Lens (ref: APO MACRO 150 mmF2.8 EX DG HSM). Pictures obtained are cropped to keep a squared regionof 400 pixels×400 pixels.

Stock Compositions

Non-limiting examples of how stock solutions are made up with andwithout API are illustrated. Other stock solutions may be made using thesame methodology by simply varying adding or omitting ingredients aswould be appreciated by one of the ordinary skills in the art.

EXAMPLES

The invention is described with reference to the following examples. Forthe purpose of the Examples below it was sufficient to apply a vacuumonly at the crimping stage although for long term stability preferablyany vacuum should be applied during manufacture as well at a sufficientpressure so that any oxygen remaining in the formulation is virtuallynegligible. This invention is not limited to these examples andexperiments. Many variations will suggest themselves and are within thefull intended scope of the appended claims.

Example 1 A Waterless Steroid Foamable Composition with out a ModulatingAgent

The components of this waterless foamable composition and the results ofthe measurements of the stability of the active agent are set our below:

Material chemical name % W/W Propylene glycol 31.60 Glycerin anhydrous37.40 Stearyl alcohol 1.00 Hydroxypropyl cellulose 1.50 Laureth-4 2.00Glyceryl Monostearate/PEG 100 Stearate 1.50 Stock Betamethasone 17- 0.12solution Valerate Propylene glycol 24.88 Total 100.00 % BMV-21 of Timepoint % of BMV-17 (w/w) BMV 0.12% (w/w) ACCELORATED CHEMICAL STABILITYTESTS FOR FOAM ZT 0.120 0.32 2 weeks, 0.079 33.98 40° C. 1 month, 40° C.0.066 40.07 ACCELORATED CHEMICAL STABILITY TESTS FOR PRE- FOAMFORMULATION ZT 0.120 0.63 2 weeks, 0.059 51.33 50° C. 1 month, 50° C.0.036 41.77

Comment: Significant amounts of BMV-17 break down into its unwantedisomer BMV-21 within a relatively short period of time in the absence ofa Modulating agent. For foam, a propellant, which is a mixture ofpropane, butane and isobutane was added at 8% by weight of the totalcomposition.

Example 2 Waterless Steroid Foamable Compositions where the ModulatingAgent is a Citric Acid/Sodium Citrate buffer

The components of these waterless foamable compositions and the resultsof measurements of the properties of the resultant foams and of thestability of the active agent are set our below:

a) At 0.1% Sodium Citrate

Material chemical name % W/W Propylene glycol 31.00 Glycerin anhydrous37.40 Stearyl alcohol 1.00 Hydroxypropyl cellulose 1.50 Laureth-4 2.00Glyceryl Monostearate/PEG 100 Stearate 1.50 Citric acid 0.50 Sodiumcitrate 0.10 Stock Betamethasone 17- 0.12 solution Valerate Propyleneglycol 24.88 Total 100.00 Results Quality good Color white Odor No odorHardness [g] 66.98 Collapse time at 36° C. [sec] >300 % BMV-21 of BMVTime point % of BMV-17 (w/w) 0.12% (w/w) ACCELORATED CHEMICAL STABILITYTESTS FOR FOAM ZT 0.117 0.90 2 weeks, 0.118 0.42 40° C. 1 month, 40° C.0.111 0.47 ACCELORATED CHEMICAL STABILITY TESTS FOR PRE- FOAMFORMULATION ZT 0.118 0.95 2 weeks, 0.115 1.34 50° C. 1 month, 50° C.0.109 1.40

Comment: In the presence of a modulating agent BMV-17 does notsignificantly break down into its unwanted isomer BMV-21 over a periodof a month of accelerated stability tests indicating that the formulawill be stable in the long term. The presence of a classical buffer inthe waterless composition of the present invention is effective in a nonclassical way in providing a chemically stable environment for theactive agent. It will be noted that the formulation produced goodquality breakable foam with typical physical parameters of a polarwaterless foam. For foam, a propellant, which is a mixture of propane,butane and isobutane was added at 8% by weight of the total composition.

b) At 0.4% Sodium Citrate

Material chemical name % W/W Propylene glycol 31.00 Glycerin anhydrous37.40 Stearyl alcohol 1.00 Hydroxypropyl cellulose 1.50 Laureth-4 2.00Glyceryl Monostearate/PEG 100 Stearate 1.50 Citric acid 0.50 Sodiumcitrate 0.40 Stock Betamethasone 17- 0.12 solution Valerate Propyleneglycol 24.88 Total 100.00 % BMV-21 of BMV Time point % of BMV-17 (w/w)0.12% (w/w) CHEMICAL STABILITY TESTS FOR FOAM ZT 0.122 0.00 2 weeks,0.117 0.82 40° C. 1 month, 40° C. 0.117 1.89 CHEMICAL STABILITY TESTSFOR PRE-FOAM FORMULATION ZT 0.122 0.00 2 weeks, 0.114 3.33 50° C. 1month, 50° C. 0.109 8.44

Comment: In the presence of a modulating agent BMV-17 does notsignificantly break down into its unwanted isomer BMV-21 over a periodof two weeks of accelerated stability study. After a month minimalbreakdown is seen indicating that the lower level of 0.1% w/w sodiumcitrate is preferable. For foam, a propellant, which is a mixture ofpropane, butane and isobutane was added at 8% by weight of the totalcomposition.

Example 3 A Waterless Steroid Foamable Composition where the ModulatingAgent is Stearic Acid

The components of this waterless foamable composition and the results ofmeasurement of the stability of the active agent are set our below:

Material chemical name % W/W Propylene glycol 30.60 Glycerin anhydrous37.40 Stearyl alcohol 1.00 Hydroxypropyl cellulose 1.50 Laureth-4 2.00Glyceryl Monostearate/PEG 100 Stearate 1.50 Stearic acid 1.00 StockBetamethasone 17- 0.12 solution Valerate Propylene glycol 24.88 Total100.00 % BMV-21 of Time point % of BMV-17 (w/w) BMV 0.12% (w/w)STABILITY TESTS FOR FOAM ZT 0.113 1.32 2 weeks, 0.112 2.20 40° C. 1month, 40° C. 0.096 2.41 STABILITY TESTS FOR PRE-FOAM FORMULATION ZT0.115 0.73 2 weeks, 0.109 4.80 50° C. 1 month, 50° C. 0.093 5.78

Comment: In the presence of a modulating agent BMV-17 does notsignificantly break down into its unwanted isomer BMV-21 over a periodof two weeks of accelerated stability. After a month only very minimaladditional breakdown is seen indicating that stability is likely to beimproved with a higher level of Stearic Acid and that the formula willbe stable in the long term. For foam, a propellant, which is a mixtureof propane, butane and isobutane was added at 8% by weight of the totalcomposition.

Example-4 A Waterless Steroid Foamable Composition with a PenetrationEnhancer

DMI in the absence of an added Modulating Agent.

The components of this waterless foamable composition and the results ofmeasurements of the properties of the resultant foam and of thestability of the active agent are set our below:

a) Composition and Physical Results

% w/w Ingredient Stearyl alcohol 1.00 Laureth-4 2.00 Glyceryl stearate &PEG-100 1.50 stearate Propylene glycol 45.88 Hydroxypropyl cellulose1.50 Glycerin anhydrous 33.00 Dimethyl isosorbide 15.00 Betamethasone17-valerate 0.12 Total: 100.00 Propellant: Mixture of propane, 8.00butane, isobutane* Results Quality good Color white Odor no odorDensity[g/mL] 0.089 Hardness [g] 94.610 Expansion time [sec] 90 secCollapse time at 36° C. [sec] >300

b) Betamethasone Valerate Waterless Results Showing Stability at ThreeMonths

T-0 T-3 Temp (w/w)% 0.117 0.113 25 C. 0.117 0.113 40 C. Percentage of100.000 96.581 25 C. original 100.000 96.581 40 C.

Comment: The above formula, in retrospect, was noted to have containedsignificant levels of residues of fatty acids, which were present in theraw materials. Nevertheless, the active ingredient did not significantlybreak down over a period of three months of accelerated stabilityindicating that the formula will be stable in the long term. Thus, thepresence of acidic residues unexpectedly contributed to the stability ofthe active ingredient and it is postulated that the stabilizing effectin the above formula is a combination of the absence of water coupledwith the presence of acidic residues in the formulation and weaklyacidic properties of the surfactants. In contrast the formula of Example1 utilizing pure grade raw materials with practically no acidic residuesundergoes a relatively rapid and serious breakdown.

Example 5 A Waterless Vitamin D3 Derivative Foamable Composition wherethe Modulating Agent is Triethoanolamine

The components of these waterless foamable compositions and the resultsof measurements of the properties of the resultant foams and of thestability of the active agent are set our below:

-   -   A. Where the waterless solvent is a combination of two        polyethylene glycols:

Ingredient name Concentration (INCI, CTFA) (% w/w) Calcipotriol 0.005Polyethylene 65 glycol 400 Polyethylene 32.925 glycol 200 Hydroxypropyl0.5 cellulose Steareth-2 1.5 Triethanolamine 0.07 Results T-0 QualityGood Color White Odor No odor Density 0.096

-   -   B. Where the waterless solvent is a combination of two        polyethylene glycols and propylene glycol:

Ingredient name Concentration (INCI, CTFA) (% w/w) Calcipotriol 0.005Polyethylene 65 glycol 400 Polyethylene 27 glycol 200 Propylene glycol4.895 Hydroxypropyl 1.5 cellulose Steareth-2 1.5 Triethanolamine 0.1Results T-0 Quality Good Color White Odor No odor Density 0.096

-   -   C. Where the waterless solvent is propylene glycol:

Ingredient name (INCI, Concentration CTFA) (% w/w) Calcipotriol 0.005Propylene 87.895 glycol Stearyl alcohol 2 Hydroxypropyl 2 celluloseLaureth-4 2 Glyceryl 2 monostearate Ceteareth-20 1 PPG-15 Stearyl 3ether Triethanolamine 0.1 Results T-0 Quality Good Color White Odor Noodor Density 0.064

Comment: The above three formulations demonstrate waterless breakablefoams of good quality in which the active ingredient is sensitive to thepresence of water and light and is stabilized by the absence of watercoupled with the presence of a modulating agent triethanolamine. As willbe appreciated from the results the physical characteristics are littlevaried following variations in the waterless solvent. Moreover, it canbe seen that waterless foamable pharmaceutical and cosmetic compositionsof good quality can be achieved with minimal ingredients comprising awaterless solvent, a surfactant, a polymeric agent, a propellant and aneffective amount of an active ingredient. For foam, a propellant, whichis a mixture of propane, butane and isobutane was added at 8% by weightof the total composition. In the above examples the propellant was AP70.

Example 6 A Waterless Ascorbic Acid Foamable Composition

The components of these waterless foamable compositions and the resultsof measurements of the properties of the resultant foam and of thestability of the active agent are set our below:

Ingredient name (INCI, CTFA) 1 2 3 4 Propylene glycol 88.00 78.00 46.0078.00 Glycerin anhydrous 33.00 10.00 Stearyl Alcohol 2.00 1.00 1.00 2.00Hydroxypropyl Cellulose 2.00 1.50 1.50 2.00 Laureth-4 2.00 2.00 2.002.00 Glyceyl Monostearate/ 1.50 PEG 100 Stearate GMS NE 2.00 1.00 2.00Macrogol Cetostearyl ether 1.00 1.50 1.00 PPG-15 stearyl ether 3.00 3.00Dimethyl isosorbide 15.00 15.00 total 100.00 100.00 100.00 100.00Ingredient name (INCI, CTFA) % w/w % w/w % w/w % w/w Stock Gel Phasepreparation 95.00 95.00 95.00 95.00 Ascorbic Acid 5.00 5.00 5.00 5.00Propellant 8.00 8.00 8.00 8.00 RESULTS FOAM QUALITY GOOD GOOD GOOD GOODCOLOR WHITE WHITE WHITE WHITE ODOR NO ODOR ODOR NO ODOR ODOR SHAKABILITYMODERATE MODERATE MODERATE MODERATE DENSITY 0.08 0.09 0.10 0.08 COLLAPSETIME >300 >300 >300 >300 HARDNESS Not Not 52.25 36.04 measured measured

Comments; the above formulations demonstrate the preparation of goodquality foam containing ascorbic acid as active ingredient is notsignificantly influenced by the addition of a secondary solvent or thepresence of a penetration enhancer Dimethyl isosorbide. To an extentascorbic acid may act as its own modulating agent. Another modulatingagent can be used to modify the artificial pH to be of the order of thepH at which ascorbic acid is most stable.

Example 7 Waterless Lidocaine HCl-Prilocaine Base Foamable Composition

The components of this waterless foamable composition and the results ofmeasurements of the properties of the resultant foam and of thestability of the active agent are set our below:

% W/W Material chemical name Propylene glycol 46.00Hydroxypropylcellulose EF 1.50 Stearyl alcohol 1.00 Laureth-4 2.00Glyceryl Stearate (and) PEG-100 1.50 Stearate Lidocaine HCl 2.50Prilocaine base 2.50 Glycerin anhydrous 28.00 Dimethyl isosorbide 15.00Total: 100.00 Mixture of Propane/Butane/Isobutane 8.00 RESULTS FOAMQUALITY GOOD COLOR WHITE ODOR NO ODOR SHAKABILITY GOOD COLLAPSETIME >300 HARDNESS 85.88

Comments; the above formulations demonstrate the preparation of goodquality foam containing anesthetics as active ingredient is notsignificantly influenced by the addition of a secondary solvent or thepresence of a penetration enhancer Dimethyl isosorbide. To an extentlidocaine and prilocaine may act as its own modulating agent. Anothermodulating agent can be used to modify the artificial pH to be of theorder of the pH at which lidocaine and prilocaine are respectively moststable.

Example 8 A Minimal Waterless Carrier

The components of this waterless foamable composition and the results ofmeasurements of the properties of the resultant foam and of thestability of the active agent are set our below:

% W/W Material chemical name Propylene glycol 96.00 Hydroxypropylcellulose 2.00 Steareth 2 2.00 Total 100.00 Results quality excellentcolor white odor no odor

Comment: this carrier produces an excellent foam. Addition of an activeagent such as active steroids in low concentrations of the order of 0.01to 0.5% for example BMV at 0.12% w/w. together with a modulating agentshould have minimal effect on the physical characteristics of theresultant foam.

Example 9 Demonstration of Excellent Minimal Foams Produced with TwoDifferent Surfactants Steareth 2 and Montanov 68 (Cetearyl Alcohol andCetearyl Glucoside)

The components of these waterless foamable compositions and the resultsof measurements of the properties of the resultant foams and of thestability of the active agent are set our below:

Material chemical name % W/W % W/W % W/W Propylene glycol 96.00 95.2897.50 Hydroxypropyl cellulose 2.00 2.00 0.50 Steareth 2 2.00 2.00 Citricacid 0.50 Sodium citrate 0.10 Cetearyl Glucoside and 2.00 CetearylAlcohol Betamethasone 17-Valerate 0.12 Results Total 100.00 100.00100.00 quality excellent excellent excellent color white white whiteodor no odor no odor no odor shakability shakable shakable shakable

Comments; the above formulations demonstrate the preparation ofexcellent quality foams using two different non ionic surfactants andthat the addition of buffer or active agent has no significant effect onfoam quality. For foam, a propellant, which is a mixture of propane,butane and isobutane was added at 8% by weight of the total composition.

Example 10 Examples of Foams Containing a Steroid Active Agent withCarbomer (Synthetic High Molecular Weight Crosslinked Polymers ofAcrylic Acid) as the Polymeric Agent

The components of these waterless foamable compositions and the resultsof measurements of the properties of the resultant foams and of thestability of the active agent are set our below:

Material chemical name % W/W % W/W % W/W % W/W % W/W % W/W Propylene97.50 97.45 97.60 97.575 97.50 97.45 97.60 97.60 glycol Steareth 2 2.002.00 2.00 2.00 Carbomer 934 0.50 0.50 0.20 0.20 0.50 0.50 0.20 0.20triethanolamine 0.20 0.20 0.20 0.20 Cetearyl 2.00 2.00 Glucoside andCetearyl Alcohol Methyl glucose 2.00 sesquistearate Span 60 2.00Clobetasol 0.05 0.05 propionate Flucinolone 0.025 acetonide Total 100.00100.00 100.00 100.00 100.00 100.00 Results Quality .E E E E E eE .G .G E= excellent G = good Color White white White white white white whitewhite Odor no odor no odor no odor no odor no odor no odor no odor noodor Shakability yes. yes .yes .yes .yes .yes .yes yes

Comments; the above formulations demonstrate the preparation ofexcellent quality foam using Carbomer (synthetic high molecular weightcrosslinked polymers of acrylic acid) Carbomer is acidic in nature andcan stabilize an active agent atone or in combination with an organicbase such as triethanolamine. For foam, a propellant, which is a mixtureof propane, butane and isobutane was added at 8% by weight of the totalcomposition.

Example 10 Chemical Stability a) Stock Solutions 1 and 2

chemical name Stock 1 Stock 2 Stearyl alcohol 1.00 Laureth-4 2.00Glyceryl stearate & PEG-100 1.50 stearate Propylene glycol 36.00 9.88Hydroxypropyl cellulose 1.50 Glycerin anhydrous 33.00 Steareth 2Dimethyl isosorbide 15.00 Betamethasone 17-valerate 0.12 Total 90.0010.00

Comments: 90 mls of Stock 1 was combined with 10 mls of stock 2 toproduce the basic formulations of 3, 4 and 5 below to which only a fewdrops of acidic Modulating Agent was added as indicated below.

b) 46% Waterless PG Formulations with BMV with different acidicModulating Agents including one where the modulating agent is a secondactive agent

chemical name 003 004 005 Stearyl alcohol 1.00 1.00 1.00 Laureth-4 2.002.00 2.00 Glyceryl stearate & PEG-100 1.50 1.50 1.50 stearate Propyleneglycol (PG) 45.88 45.88 45.88 Hydroxypropyl cellulose 1.50 1.50 1.50Glycerin anhydrous 33.00 33.00 33.00 Dimethyl isosorbide 15.00 15.0015.00 Betamethasone 17-valerate 0.12 0.12 0.12 (BMV) Lactic acid* To ph4-4.5 L-Glutamic acid* To ph 4-4.5 Azelaic acid* To ph 4-4.5 Total100.00 100.00 100.00 Propellant (AP-70) 8.00 8.00 8.00 foam quality GoodGood Good Color White White White Odor No No No assay (T-0) FOAM 0.11830.1183 0.1177 assay (T-1M) 5 C FOAM 0.1180 0.1182 0.1181 assay (T-1M) 25C FOAM 0.1175 0.1185 0.1180 assay (T-1M) 40 C FOAM 0.1158 0.1156 0.1165assay (T-1M) 50 C PFF 0.1148 0.1165 0.1158 *Only a few drops wererequired to achieve the required pH, which was sufficient to provide astabilizing effect.

Comments: All the modulated formulations provided foam of good quality,in which the active agent BMV was shown to be stable to degradation in awide range of temperature from 5 C to 50 C over a period of a month. Thepre foam formulation was also found to be stable for 1 month.

Example 11 EDTA

chemical name 006 007 Propylene glycol 97.90 98.90 Hydroxypropylcellulose 1.00 Steareth 2 2.00 EDTA 0.10 0.10 Total 100.00 100.00Propellant (AP-70) 8.00 8.00 foam quality Good Good Color White WhiteOdor No No

Comments: The formulation is modulated with EDTA and provided foam ofgood quality.

Example 12 Lysine

chemical name 008 Propylene glycol 98.00 Steareth 2 2.00 L-lysine To ph7 Total 100.00 Propellant (AP-70) 8.00 foam quality Good Color WhiteOdor No

Comments: The formulation modulated with a basic Modulating Agentprovided foam of good quality,

Example 13 BMV

a) Minimum Ingredients;

chemical name 009 010 Stearyl alcohol 1.00 Laureth-4 2.00 Glycerylstearate & PEG-100 1.50 stearate Propylene glycol 45.88 97.88Hydroxypropyl cellulose 1.50 Glycerin anhydrous 33.00 Steareth 2 2.00Dimethyl isosorbide 15.00 Betamethasone 17-valerate 0.12 0.12 Total100.00 100.00 Propellant (AP-70) 8.00 8.00 Viscosity 4990.94 3711.21foam quality Good Good Color White White Odor No No Density 0.07 0.05Collapse time >300/G .300/G BUBBLE SIZE (μm) 150 139 BUBBLE SIZE (above500 μm) 3.4 3.7 Conductivity 0.41 μS   0 μS Conductivity (+1 drop ofLactic acid) 0.55 μS 0.05 μS

Comments: It is surprisingly possible to produce good quality foamwithout a polymeric agent. Nevertheless, the presence of polymeric agentcan be not only helpful but important and sometimes critical for foamstability. Prophetically, small amounts of modulating agent may be addedto the formulations without significant effect on the resultant foam.Remarkably, despite that these formulations are waterless, neverthelessa single drop of lactic acid results in a significant increase ofconductivity. Also as can be seen herein the use of modulating agents isjust as applicable for formulations with minimal ingredients as it iswith complex formulations, perhaps the main difference being that withcomplex formulations the there are more ingredients which increases therisk that one may contain a small impurity that can result indestabilization of the active ingredient. On the other hand formulationswith few ingredients may have higher levels of a destabilizing impuritymerely because say 90% of the formulation comprises an ingredient havingthe impurity albeit at low levels. Either way the importance of thepresence of a small amount of modulating agent in a waterlessformulation cannot be ignored or underestimated.

b) Focus Group (5)

Sum Avg STDV TOTAL MAPG009P ease of application 21 4.2 0.45 180 foamTexture 20 4 0.00 foam stability on hand 24 4.8 0.45 absorbance (1 min.)17 3.4 0.55 spreadability 21 4.2 0.45 greasy feeling 16 3.2 1.10 (after1-2 min.) shiny look 18 3.6 1.14 (after 1-2 min.) stickiness (after 1-2min.) 17 3.4 1.14 odor 10 2 1.73 total satisfaction 16 3.2 1.10 MAPG010Pease of application 21 4.2 0.84 201 foam Texture 20 4 0.71 foamstability on hand 22 4.4 0.55 absorbance (1 min.) 19 3.8 1.10spreadability 21 4.2 0.84 greasy feeling 19 3.8 1.30 (after 1-2 min.)shiny look 18 3.6 1.14 (after 1-2 min.) stickiness (after 1-2 min.) 183.6 1.14 odor 22 4.4 0.55 total satisfaction 21 4.2 0.84

Comments: The total satisfaction was surprisingly found to besignificantly greater with the formulation with minimal ingredients.

Example 14 Carbopol and TEA

chemical name 011 012 Propylene glycol 99.00 97.00 Carbopol 934 1.001.00 Steareth 2 2.00 Triethanolamine (TEA) neutralization (1neutralization (1 drop) drop) Total 100.00 100.00 Propellant (AP-70)8.00 8.00 Viscosity 13485.12 foam quality P Good Color White White OdorNo No Density 0.08 Collapse time >300/G BUBBLE SIZE (μm) 72 BUBBLE SIZE(above 500 μm) 0.0

Comments: The formulation modulated with an acidic polymer and a basicModulating Agent TEA provided foam of good quality, Carbomer is across-linked polymer of acrylic acid with a high molecular weight.

Example 15 Stearic Acid

chemical name 013 014 Stearic acid 5.00 3.00 Isostearic acid 3.00Propylene glycol 95.00 94.00 Total 100.00 100.00 Propellant (AP-70) 8.008.00 Viscosity 1887.60 foam quality Good P Color White White Odor No NoDensity 0.30 Collapse time >300/G

Comments: Stearic acid a waxy solid acts as a foam adjuvant, thickenerand Modulating Agent to produce good quality foam. The selection ofModulating Agent is not per se obvious with a waterless formulation. Forexample, the addition of isostearic acid results in poor foam presumablybut without being bound by any theory suggested due to it being a liquidwax and not having the thickening effect of its closely relatedcounterpart stearic acid plus its isostearic acids asymmetrical shapeeven though they both are CI8.

1. A waterless composition comprising one or more active agents and acarrier for topical delivery of the one or more active agents suitablefor stabilizing at least one of said one or more active agents, saidcarrier comprising a waterless solvent and an effective amount of amodulating agent; wherein the at least one active agent is chemicallyunstable in the carrier in the absence of a modulating agent; whereinthe modulating agent is capable of and is selected to modulate or adjustthe artificial pH of the carrier to an artificial pH or to provide anartificial pH buffering effect such that the chemical stability of theat least one active agent is increased as compared to its stability inthe carrier without the modulating agent.
 2. The waterless compositionof claim 1 further comprising one or more agents that additionally arecapable of a function selected from the group consisting of chelating anavailable metal ion, impeding ionization, and impeding oxidation.
 3. Thewaterless composition of claim 1 wherein the waterless solvent comprisesabout 25% to about 98% of at least polar solvent selected from the groupconsisting of (1) a polyol; and (2) a polyethylene glycol orcombinations thereof.
 4. The waterless composition of claim 3 furthercomprising a stabilizing agent selected from the group consisting of asurface-active agent; about 0.01% to about 5% by weight of at least onepolymeric agent and mixtures thereof.
 5. The waterless composition ofclaim 1 wherein an effective amount of modulating agent is between about5% to about 0.01% by weight of the composition and wherein if the activeagent itself has a modulating effect the amount of active agent used toobtain an effective modulating effect is less than the amount used toobtain an effective therapeutic effect.
 6. The waterless composition ofclaim 5 wherein an effective amount of modulating agent is between about1% to about 0.02% by weight of the composition.
 7. The waterlesscomposition of claim 1 wherein an effective amount of modulating agentis between about 0.6% to about 0.04% by weight of the composition. 8.The waterless composition of claim 1 wherein an effective amount ofmodulating agent is between about 1 to about 5 drops.
 9. A foamablewaterless composition comprising: a. a therapeutically effectiveconcentration of one or more active agents; b. a carrier for topicaldelivery of the one or more active agents suitable for stabilizing atleast one of said one or more active agents, comprising i. about 25% toabout 98% of at least polar solvent selected from the group consistingof (1) a polyol; and (2) a polyethylene glycol; ii. 0% to about 75% of asecondary polar solvent; iii. an effective amount of a modulating agentiv. a stabilizing agent selected from the group consisting of asurface-active agent; about 0.01% to about 5% by weight of at least onepolymeric agent and mixtures thereof. v. a liquefied or compressed gaspropellant at a concentration of about 3% to about 25% by weight of thetotal composition wherein the at least one active agent is chemicallyunstable in the carrier in the absence of a modulating agent; whereinthe modulating agent is capable of and is selected to modulate or adjustthe artificial pH of the carrier to an artificial pH or to provide anartificial pH buffering effect such that the chemical stability of theat least one active agent is increased as compared to its stability inthe carrier without the modulating agent. wherein the carrier isshakable or flowable; and wherein the composition is stored in anaerosol container and upon release expands to form a breakable foam. 10.The waterless composition of claim 9, wherein the breakable foam is ofabout good quality.
 11. The waterless composition of claim 9, whereinthe modulating agent is selected from the group consisting of sodiumcitrate, citric acid, lactic acid, glutamic acid, ascorbic acid,azalaeic acid, stearic acid, triethanolamine, lysine, lidocaine,prilocaine, carbomer and mixtures thereof.
 12. The foamable compositionof claim 9, wherein the composition is substantially non-aqueous. 13.The foamable composition of claim 9, wherein the polyol is selected fromthe group consisting of a diol; a triol; at least one diol and at leastone triol, wherein the ratio between the diol and triol is between 9:1and 1:1; a saccharide; and mixtures thereof.
 14. The foamablecomposition of claim 13, wherein the diol is selected from the groupconsisting of propylene glycol, butanediol, butenediol, butynediol,pentanediol, hexanediol, octanediol, neopentyl glycol,2-methyl-1,3-propanediol, diethylene glycol, triethylene glycol,tetraethylene glycol, dipropylene glycol and dibutylene glycol; and orwherein the triol is selected from the group consisting of glycerin,butane-1,2,3-triol, butane-1,2,4-triol and hexane-1,2,6-triol.
 15. Thefoamable composition of claim 9, wherein the PEG is selected from thegroup consisting of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG4000, PEG 6000 and PEG
 8000. 16. The foamable composition of claim 9,wherein the foamable carrier comprises one or more PEGs in aconcentration to provide viscosity of less than 12,000 CPs.
 17. Thefoamable composition of claim 9, wherein the carrier compositioncomprises a mixture of at least one polyol and at least one PEG.
 18. Thefoamable composition of claim 9, wherein the secondary polar solvent isselected from the group consisting of dimethyl isosorbide,tetrahydrofurfuryl alcohol polyethyleneglycol, ether, DMSO, apyrrolidone, N-Methyl-2-pyrrolidone, 1-Methyl-2-pyrrolidinone, ethylproxitol, dimethylacetamide, a PEG-type surfactant, an alpha hydroxyacid, lactic acid and glycolic acid.
 19. The foamable composition ofclaim 9, wherein the carrier composition comprises (1) at least onepolar solvent selected from a diol, a triol and PEG, and (2) at leastone secondary polar solvent.
 20. The foamable composition of claim 9,wherein the ratio between the polyol and/or PEG and the secondary polarsolvent is between 9:1 and 1:4.
 21. The foamable composition of claim 9,wherein the composition is substantially alcohol-free.
 22. The foamablecomposition of claim 9, wherein the modulating agent is selected fromthe group consisting of an alpha hydroxyl acid, an aliphatic betahydroxyacid, an aromatic acid, an aromatic hydroxyl acid, an alphaketoacid, an aliphatic carboxylic acid, a branched aliphatic carboxylicacid, a short chain carboxylic acid, a fatty acid, an omega-3 fattyacid, an omega-6 fatty acid, an omega-9 fatty acid, a dicarboxylic acid,a branched dicarboxylic acid, an unsaturated dicarboxylic acid, an aminoacid, a dimer or oligomer of amino acids, a retinoid, anitrogen-containing organic compound, a primary, secondary, tertiary andquaternary amine, an amide, an amine oxide and a lactam.
 23. Thefoamable composition of claim 22, wherein the alpha hydroxyl acid andbetahydroxyl acid are selected from the group consisting ofalpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid,alpha-hydroxyisocaproic acid, alpha-hydroxyisovaleric acid, atrolacticacid, beta-hydroxybutyric acid, beta-phenyl lactic acid,beta-phenylpyruvic acid, citric acid, pyruvic acid, galacturonic acid,glucoheptonic acid, glucoheptono 1,4-lactone, gluconic acid,gluconolactone, glucuronic acid, glucuronolactone, glycolic acid, lacticacid, mandelic acid, mucic acid, pyruvic acid, saccharic acid, saccharicacid 1,4-lactone, tartaric acid and tartronic acid, 3-Hydroxybutanoicacid, quinic acid, isocitric acid, tropic acid, trethocanic acid,chlorolactic acid, citramalic acid, agaricic acid, aleuritic acid,pantoic acid, lactobionic acid, piscidic acid, hexylosonic acid or theanhydride thereof; wherein the aromatic acid is selected from the groupconsisting of benzoic acid, toluic acid, dimethyl benzoic acid andphthalic acid; wherein the beta hydroxyl acid is selected from the groupconsisting of salicylic acids and derivatives thereof; wherein the alphaketoacid has the molecular structure of (R_(a))COCOO(R_(b)); whereinR_(a) and R_(b) are independently selected from the group consisting ofH and saturated or unsaturated, isomeric or non-isomeric, straight,branched, or cyclic C1-C25 alkyl, aralkyl, or aryl groups, wherein R_(a)may be optionally substituted with an F, Cl, Br, I, OH, CHO, COOH, oralkoxy group having 1 to 9 carbon atoms; wherein the aliphaticcarboxylic acid is selected from the group consisting of formic acid,acetic acid and propionic acid, butyric acid, butyric acid, caproicacid, caprylic acid, nonanoic acid, capric acid, lauric acid, myristicacid, palmitic acid, stearic acid, arachidic acid, behenic acid,octacosanoic acid, oleic acid, linoleic acid, alpha-linolenic acid,arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, erucicacid, valproic acid and 12-hydroxy stearic acid; wherein thedicarboxylic acid is selected from the group consisting of oxalic acid,malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid,suberic acid, azelaic acid, sebacic acid, dodecanedioic acid, brassylicacid, thapsic acid, 14-methylnonacosanedioic acid,14,15-dimethyltriacontanedioic acid (C30) undecylenic acid, maleic acidand fumaric acid; wherein the carbon atom skeleton of the brancheddicarboxylic acid is substituted with at least one group selected fromthe group consisting of R, F, Cl, Br, OH, OR, SH, CHO, COOH, andNR_(a)R_(b), ansd wherein R, R_(a) and R_(b) are independently selectedfrom the group consisting of H, saturated or unsaturated, isomeric ornon-isomeric, straight, branched, or cyclic C1-C25 alkyl, aralkyl, oraryl groups; wherein the branched dicarboxylic acid is selected from thegroup consisting of aspartic acid, alpha-ketoglutaric acid, adipic acid2-amino, aconitic acid, benzene dicarboxylic acid, citramalic acid,citric acid, cystathionine, glucuronic acid, glutamic acid, itaconicacid, malic acid, mucic acid, oxalacetic acid, diamino pimelic acid,saccharic acid, dimethyl succinic acid, tartaric acid and tartronicacid; wherein the carboxylic acid is selected from the group consistingof is selected from the group consisting of retinoic acid, isotretinoin,ascorbic acid, isoascorbic acid, ethanesulfonic acid, glycerophosphoricacid, acetohydroxamic acid, aconitic acid, alpha-ketocaproic acid,aminomalonic acid, hippuric acid, hydrochloric acid, methanesulfonicacid, oxalic acid, phosphoric acid, sorbic acid, iminodiacetic acid andcarnitine; and wherein the amino acid is selected from the groupconsisting of glycine, alanine, valine, leucine, isoleucine, serine,threonine, cysteine, methionine, aspartic acid, asparagine, glutamicacid, glutamine, arginine, lysine, histidine, phenylalanine, tyrosine,tryptophan, praline, B-alanine (3-alanine), 4-aminobutyrate (GABA),3-cyanoalanine (B-cyanoalanine), 2-aminobutyric acid,2-methylene-4-aminobutyric acid, 3-methylene-4-aminobutyric acid,2-aminoisobutyric acid, 5-aminolevulinic acid, 2-amino-4-methylhexanoicacid (homoisoleucine), 2-amino-4-methylhex-4-enoic acid,2-amino-4-methylhex-5-ynoic acid, 2-amino-3-methylpentanoic acid,2-aminoadipic acid, 4-ethylideneglutamic acid, 3-aminoglutaric acid,2-aminopimelic acid, N4-ethylasparagine, N4-methylasparagine,erythro-4-methylglutamic acid, 4-methyleneglutamic acid,4-methyleneglutamine, N5-methylglutamine, N5-ethylglutamine (theanine),N5-isopropylglutamine, 2-amino-4-(aminoxy) butyric acid (canaline),2,4-diaminobutyrate, N4-acetyl-2,4-diaminobutyrate,N4-lactyl-2,4-diaminobutyrate, N4-oxalyl-2,4-diaminobutyrate,2,3-diaminopropionic acid, N3-acetyl-2,3-diaminopropionic acid,N3-methyl-2,3-diaminopropionic acid, N3-oxalyl-2,3-diaminopropionicacid, N6-acetyllysine, N6-methyllysine, N6-trimethyllysine (laminine),ornithine (2,5-diaminopentanoic acid), saccharopine(N6-(2′-glutamyl)lysine, 2,6-diaminopimelic acid,N4-(2-hydroxylethyl)asparagine, erythro-3-hydroxyaspartic acid,4-hydroxyarginine, 4-hydroxycitrulline, threo-4-hydroxyglutamic acid,3,4-dihydroxyglutamic acid, 3-hydroxy-4-methylglutamic acid,3-hydroxy-4-methyleneglutamic acid, 4-hydroxy-4-methylglutamic acid,4-hydroxy-glutamine, N5-(2-hydroxyethyl)glutamine, 5-hydroxynorleucine,threo-4-hydroxyhomoarginine, homoserine, O-acetylhomoserine,O-oxalylhomoserine, O-phosphohomoserine, 4-hydroxyisoleucine,5-hydroxymethylhomocysteine, threo-3-hydroxyleucine, 5-hydroxyleucine,2-hydroxylysine, 4-hydroxylysine, 5-hydroxylysine,N6-acetyl-5-hydroxylysine, N6-trimethyl-5-hydroxylysine,4-hydroxyornithine, mimosine, 4-hydroxynorvaline, 5-hydroxynorvaline,2-amino-4,5-dihydroxypentanoic acid, 2-amino-4-hydroxypimelic acid,4-hydroxyvaline, O-acetylserine, O-phosphoserine, pipecolic acid,(piperidine-2-carboxylic acid), 3-hydroxypipecolic acid,trans-4-hydroxypipecolic acid, trans-5-hydroxypipecolic acid,5-hydroxy-6-methylpipecolic acid, 4,5-dihydroxypipecolic acid,trans-3-hydroxyproline, trans-4-hydroxyproline,trans-4-hydroxymethylproline, azetidine-2-carboxylic acid,N-(3-amino-3-carboxypropyl)azetidine-2-carboxylic acid,4,5-dehydropipecolic acid (baikiain), 3-amino-3-carboxypyrrolidone(cucurbitine), 2-(cyclopent-2′-enyl)glycine, 5-hydroxytryptophan,albizziine (2-amino-3-ureidopropionic acid), arginosuccinic acid,canavinosuccinic acid, citrulline, homoarginine, homocitrulline,indospicine, O-ureidohomoserine, 6-hydroxykynurenine,3-(4-aminophenyl)alanine, 3-(3-aminomethylphenyl)alanine,3-(3-carboxyphenyl)alanine, 3-carboxytyrosine,3-(3-hydroxymethylphenyl)alanine, 3-(3-hydroxyphenyl)alanine,3-(3,4-dihydroxyphenyl)alanine (L-DOPA), 2-(phenyl)glycine,2-(3-carboxyphenyl)glycine, 2-(3-carboxy-4-hydroxyphenyl)glycine,2-(3-hydroxyphenyl)glycine, 2-(3,5-dihydroxyphenyl)glycine,4-aminopipecolic acid, guvacine,2-amino-4-(isoxazolin-5-one)-2-yl)butyric acid, lathyrine,tetrahydrolathyrine and ornithin and dimers or oligomers thereof. 24.The foamable composition of claim 22, wherein the modulating agent is anitrogen-containing organic compound selected from the group consistingof primary amines, methylamine and ethylamine; an ethanolamine,monoethanolamine, monoisopropanolamines, a diamine, ethylenediamine,1,2-diaminopropane, a dialkylamine, dimethylamine, diethylamine,diethanolamine, diisopropanolamine, N-methylethanolamine,N-ethylethanolamine, a tertiary amine, a trialkylamine, triethylamine,triethylamine, triethanolamine, N-methyldiethanolamine andtri-isopropanolamine.
 25. The foamable composition of claim 9, whereinthe polymeric agent is selected from the group consisting of locust beangum, sodium alginate, sodium caseinate, egg albumin, gelatin agar,carrageenin gum, sodium alginate, xanthan gum, quince seed extract,tragacanth gum, guar gum, cationic guars, hydroxypropyl guar gum,starch, an amine-bearing polymer, chitosan, alginic acid, hyaluronicacid, a chemically modified starch, a carboxyvinyl polymer,polyvinylpyrrolidone, polyvinyl alcohol, a polyacrylic acid polymer, apolymethacrylic acid polymer, polyvinyl acetate, a polyvinyl chloridepolymer, a polyvinylidene chloride polymer, methylcellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose,methyl hydroxypropylcellulose, hydroxyethylcarboxymethylcellulose,carboxymethyl cellulose, carboxymethylcellulosecarboxymethylhydroxyethylcellulose, a cationic cellulose PEG 1000, PEG4000, PEG 6000 and PEG 8000, carbomer Carbopol® 934, Carbopol® 940,Carbopo® 941, Carbopol® 980 and Carbopol®
 981. 26. The foamablecomposition of claim 9, wherein the polymeric agent is dispersible inthe polyol or in the mixture of a polyol and an additional polarsolvent. The foamable composition of claim 4, wherein the concentrationof the polymeric agent is selected such that the viscosity of thecomposition is less than 12,000 CPs, or less than 10,000 CPs.
 27. Thefoamable composition of claim 9, wherein the surfactant comprises atleast one surfactant selected from the group consisting of apolyoxyethylene fatty ether, a polyoxyethylene fatty ester, acarbohydrate ester and a sucrose ester, glyceryl stearate, PEG-100stearate, steareth-2, steareth-20, steareth-21, ceteareth 2, PEG-100stearyl ether, cetearyl glucoside, methyl glucose sesquistearate,sorbitan monostearate, GMS NE, span 20, glyceryl stearate and PEG 100stearate, glyceryl stearate and PEG 100 stearate and laureth4; steareth2, PEG 100 searate and laureth4, and cetearyl glucoside and cetearylalcohol.
 28. The foamable composition of claim 9, wherein the surfaceactive agent comprises a non-ionic surface active agent.
 29. Thefoamable composition of claim 28, wherein the surface active agentfurther comprises an ionic surfactant, selected from the groupconsisting of a cationic surfactant, a zwitterionic surfactant, anamphoteric surfactant and an ampholytic surfactant.
 30. The foamablecomposition of claim 28, wherein the surface active agent comprises amixture of at least one non-ionic surfactant and at least one ionicsurfactant in a ratio selected from a. about 100:1 to about 6:1 b. about1:1 to about 20:1.
 31. The foamable composition of claim 9, furthercomprising a hydrophobic solvent.
 32. The foamable composition of claim31, wherein the hydrophobic solvent is selected from the groupconsisting of mineral oil, isopropyl palmitate, isopropyl isostearate,diisopropyl adipate, diisopropyl dimerate, maleated soybean oil, octylpalmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate,acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryloleate, tocopheryl linoleate, wheat germ glycerides, arachidylpropionate, myristyl lactate, decyl oleate, ricinoleate, isopropyllanolate, pentaerythrityl tetrastearate, neopentylglycoldicaprylate/dicaprate, isononyl isononanoate, isotridecyl isononanoate,myristyl myristate, triisocetyl citrate, octyl dodecanol, unsaturated orpolyunsaturated oils, such as olive oil, corn oil, soybean oil, canolaoil, cottonseed oil, coconut oil, sesame oil, sunflower oil, borage seedoil, syzigium aromaticum oil, hempseed oil, herring oil, cod-liver oil,salmon oil, flaxseed oil, wheat germ oil, evening primrose oils;essential oils; and silicone oils, such as dimethicone, cyclomethicone,polyalkyl siloxane, polyaryl siloxane, polyalkylaryl siloxane, apolyether siloxane copolymer and apoly(dimethylsiloxane)-(diphenyl-siloxane) copolymer.
 33. The foamablecomposition of claim 9, further comprising a foam adjuvant selected fromthe group consisting of a fatty alcohol, a fatty acid and a hydroxylfatty acid.
 34. The foamable composition of claim 9, further comprisingan additional component selected from the group consisting of an antiperspirant, an anti-static agent, a buffering agent, a bulking agent, achelating agent, a colorant, a conditioner, a deodorant, a diluent, adye, an emollient, fragrance, a humectant, an occlusive agent, apenetration enhancer, a perfuming agent, a permeation enhancer, apreservative, a skin penetration enhancer, a sunscreen, a sun blockingagent, a sunless tanning agent, and a vitamins.
 35. The foamablecomposition of claim 9, wherein the active agent is selected from thegroup consisting of active herbal extracts, acaricides, age spot andkeratose removing agents, allergen, analgesics, local anesthetics,antiacne agents, antiallergic agents, antiaging agents, antiinfective,antibacterials, antibiotics, antiburn agents, anticancer agents,antidandruff agents, antidepressants, antidermatitis agents,antiedemics, antifungal, antihistamines, antihelminths,antihyperkeratolyte agents, antiinflammatory agents, antiirritants,antilipemics, antimicrobials, antimycotics, antiproliferative agents,antiparasitic agents, antioxidants, anti-wrinkle agents, antipruritics,antipsoriatic agents, antirosacea agents antiseborrheic agents,antiseptic, antiswelling agents, antiviral agents, anti-yeast agents,agents that control yeast, astringents, topical cardiovascular agents,chemotherapeutic agents, corticosteroids, dicarboxylic acids,disinfectants, fungicides, hair growth regulators, hormones, hydroxyacids, immunosuppressants, immunoregulating agents, insecticides, insectrepellents, keratolytic agents, lactams, metals, metal oxides,mitocides, neuropeptides, non-steroidal anti-inflammatory agents,oxidizing agents, pediculicides, photodynamic therapy agents, retinoids,sanatives, scabicides, self tanning agents, steroids, skin whiteningagents, asoconstrictors, vasodilators, vitamins, vitamin D derivatives,flavonoids, wound healing agents and wart removers.
 36. The foamablecomposition of claim 35, wherein the steroid is selected from the groupconsisting of alclometasone dipropionate, amcinafel, amcinafide,amcinonide, beclomethasone, beclomethasone dipropionate, betamethsone,betamethasone benzoate, betamethasone dexamethasone-phosphate,dipropionate, betamethasone valerate, budesonide, chloroprednisone,chlorprednisone acetate, clescinolone, clobetasol, clobetasolpropionate, clobetasol valerate, clobetasone, clobetasone butyrate,clocortelone, cortisone, cortodoxone, craposone butyrate, desonide,desoxymethasone, dexamethasone, desoxycorticosterone acetate,dichlorisone, diflorasone diacetate, diflucortolone valerate,difluorosone diacetate, diflurprednate, fluadrenolone, flucetonide,flucloronide, fluclorolone acetonide, flucortine butylesters,fludroxycortide, fludrocortisone, flumethasone, flumethasone pivalate,flumethasone pivalate, flunisolide, fluocinolone, fluocinoloneacetonide, fluocinonide, fluocortin butyl, fluocortolone,fluorometholone, fluosinolone acetonide, fluperolone, fluprednideneacetate, fluprednisolone hydrocortamate, fluradrenolone, fluradrenoloneacetonide, flurandrenolone, fluticasone, halcinonide, halobetasol,hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate,hydrocortisone cyclopentylpropionate, hydrocortisone valerate,hydroxyltriamcinolone, medrysone, meprednisone, .alpha.-methyldexamethasone, methylprednisolone, methylprednisolone acetate,mometasone furoate, paramethasone, prednisolone, prednisone,pregnenolone, progesterone, spironolactone, triamcinolone, triamcinoloneacetonide and derivatives, esters and salts thereof; wherein theantifungal agent is selected from the group consisting of a polyene,natamycin, nystatin; an allylamine, naftifine, terbinafine; animidazole, bifonazole, clotrimazole, econazole, fenticonazole,ketocanazole, miconazole, oxiconazole; a diazole, a triazoles,fluconazole, itraconazole, terconazole, tolnaftate, ciclopirox,undecylenic acid, sulbentine, griseofulvin, Amphotericin B, flucytosine(5FC), a morpholine compound, amorolfine, and the related morpholinesand analogs, derivatives and salts thereof, and any combination thereofat a therapeutically effective concentration; and wherein theantibacterial agent is selected from the group consisting of abeta-lactam antibiotic, an aminoglycoside, an ansa-type antibiotic, ananthraquinone, an azole, metronidazole, an antibiotic glycopeptide, amacrolide, erythromycin, clindamycin, an antibiotic nucleoside, anantibiotic peptide, polymyxin B, an antibiotic polyene, an antibioticpolyether, an antibiotic quinolone, an antibiotic steroid, fucidic acid,mupirocin, chloramphenicol, a sulfonamide, tetracycline, an antibioticmetal, silver, copper, zinc, mercury, tin, lead, bismuth, cadmium,chromium, an oxidizing agent, iodine, iodate, a periodate, ahypochlorite, a permanganate, a substance that release free radicalsand/or active oxygen, a cationic antimicrobial agent, a quaternaryammonium compound, a biguanide, chlorohexidine, a triguanide, abisbiguanide, a polymeric biguanide, a naturally occurring antibioticcompound and analogs, derivatives, salts, ions and complexes thereof.37. The foamable composition of claim 9, wherein the active agent isunstable in the presence of water.
 38. The foamable composition of claim9, wherein the active agent is stable at an acidic pH range and themodulating agent is acidic.
 39. The foamable composition of claim 9,wherein the active agent is an ester, which undergoes hydrolysis atbasic pH.
 40. The foamable composition of claim 9, wherein the activeagent is a compound, which undergoes rearrangement at basic pH.
 41. Thefoamable composition of claim 9, wherein the active agent is stable at abasic pH range and the modulating agent is basic.
 42. The foamablecomposition of claim 41, wherein the active agent is selected fromvitamin D, a vitamin D analog, a vitamin D derivative.
 43. The foamablecomposition of claim 9, wherein the modulating agent is anitrogen-containing modulating agent.
 44. The foamable composition ofclaim 9, wherein the modulating agent is triethanolamine and the activeagent is calcipotriol.
 45. The foamable composition of claim 9, whereinthe modulating agent is selected from the group consisting of sodiumcitrate, citric acid, lacic acid, glutamic acid, azaleic acid, ascorbicacid, stearic acid and mixtures thereof and the active agent is bmv. 46.The foamable composition of claim 9, wherein the modulating agent isselected from the group consisting of carbomer, and triethanolamine, andmixtures thereof and the active agent is selected from the groupconsisting of clobetosol proprionate and flucinoline acetonide.
 47. Thefoamable composition of claim 9, wherein the active agent is stable atabout neutral pH range and the modulating agent is neutral.
 48. Thefoamable composition of claim 9, wherein the modulating agent is apharmaceutical or cosmetic active agent.
 49. The foamable composition ofclaim 9, comprising (1) a corticosteroid; and (2) and active agentselected from the group of an antifungal agent, an antimicrobial agent,an antiviral agent, an anti-acne agent, a vitamin D3 derivative,calcipotriol, and antipsoriasis agent, a keratolytic agent and anantiacne agent.
 50. The foamable composition of claim 9, comprising (1)a keratolytic agent; and (2) and active agent selected from the group ofa corticosteroid, an antifungal agent, an antimicrobial agent, anantiviral agent, an anti-acne agent, a vitamin D3 derivative,calcipotriol, and antipsoriasis agent, an immunomodulator, andimmunosuppressant and an antiacne agent.
 51. A method of treating adisorder of mammalian subject, comprising: administering a compositionto a target site, the composition comprising: one or more active agentsand a carrier for topical delivery of the one or more active agentssuitable for stabilizing at least one of said one or more active agents,said carrier comprising a waterless solvent and an effective amount of amodulating agent; wherein the at least one active agent is chemicallyunstable in the carrier in the absence of a modulating agent; whereinthe modulating agent is capable of and is selected to modulate or adjustthe artificial pH of the carrier to an artificial pH or to provide anartificial pH buffering effect such that the chemical stability of theat least one active agent is increased as compared to its stability inthe carrier without the modulating agent.
 52. A method of treating adisorder of mammalian subject, comprising: administering a foamablecomposition to a target site, the composition comprising: a foamablewaterless composition comprising: a. a therapeutically effectiveconcentration of one or more active agents; b. a carrier for topicaldelivery of the one or more active agents suitable for stabilizing atleast one of said one or more active agents, comprising i. about 25% toabout 98% of at least polar solvent selected from the group consistingof (1) a polyol; and (2) a polyethylene glycol; ii. 0% to about 75% of asecondary polar solvent; iii. an effective amount of a modulating agentiv. a stabilizing agent selected from the group consisting of asurface-active agent; about 0.01% to about 5% by weight of at least onepolymeric agent and mixtures thereof. v. a liquefied or compressed gaspropellant at a concentration of about 3% to about 25% by weight of thetotal composition wherein the at least one active agent is chemicallyunstable in the carrier in the absence of a modulating agent; whereinthe modulating agent is capable of and is selected to modulate or adjustthe artificial pH of the carrier to an artificial pH or to provide anartificial pH buffering effect such that the chemical stability of theat least one active agent is increased as compared to its stability inthe carrier without the modulating agent. wherein the carrier isshakable or flowable; and wherein the composition is stored in anaerosol container and upon release expands to form a breakable foam. 53.The method of claim 52, wherein the target site is selected from thegroup consisting of the skin, a body cavity, a mucosal surface, thenose, the mouth, the eye, the ear canal, the respiratory system, thevagina and the rectum.
 54. The method of claim 52, wherein the disorderis selected from the group consisting of dermatological pain,dermatological inflammation, acne, acne vulgaris, inflammatory acne,non-inflammatory acne, acne fulminans, nodular papulopustular acne, acneconglobata, dermatitis, bacterial skin infections, fungal skininfections, viral skin infections, parasitic skin infections, skinneoplasia, skin neoplasms, pruritis, cellulitis, acute lymphangitis,lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneousinfections, scalded skin syndrome, folliculitis, furuncles, hidradenitissuppurativa, carbuncles, paronychial infections, rashes, erythrasma,impetigo, eethyma, yeast skin infections, warts, molluscum contagiosum,trauma or injury to the skin, post-operative or post-surgical skinconditions, scabies, pediculosis, creeping eruption, eczemas, psoriasis,pityriasis rosea, lichen planus, pityriasis rubra pilaris, edematous,erythema multiforme, erythema nodosum, grannuloma annulare, epidermalnecrolysis, sunburn, photosensitivity, pemphigus, bullous pemphigoid,dermatitis herpetiformis, keratosis pilaris, callouses, corns,ichthyosis, skin ulcers, ischemic necrosis, miliaria, hyperhidrosis,moles, Kaposi's sarcoma, melanoma, malignant melanoma, basal cellcarcinoma, squamous cell carcinoma, poison ivy, poison oak, contactdermatitis, atopic dermatitis, rosacea, purpura, moniliasis,candidiasis, baldness, alopecia, Behcet's syndrome, cholesteatoma,Dercum disease, ectodermal dysplasia, gustatory sweating, nail patellasyndrome, lupus, hives, hair loss, Hailey-Hailey disease, chemical orthermal skin burns, scleroderma, aging skin, wrinkles, sun spots,necrotizing fasciitis, necrotizing myositis, gangrene, scarring, andvitiligo, chlamydia infection, gonorrhea infection, hepatitis B, herpes,HIV/AIDS, human papillomavirus (HPV), genital warts, bacterialvaginosis, candidiasis, chancroid, granuloma Inguinale, lymphogranlomavenereum, mucopurulent cervicitis (MPC), molluscum contagiosum,nongonococcal urethritis (NGU), trichomoniasis, vulvar disorders,vulvodynia, vulvar pain, yeast infection, vulvar dystrophy, vulvarintraepithelial neoplasia (VIN), contact dermatitis, pelvicinflammation, endometritis, salpingitis, oophoritis, genital cancer,cancer of the cervix, cancer of the vulva, cancer of the vagina, vaginaldryness, dyspareunia, anal and rectal disease, anal abscess/fistula,anal cancer, anal fissure, anal warts, Crohn's disease, hemorrhoids,anal itch, pruritus ani, fecal incontinence, constipation, polyps of thecolon and rectum; and wherein the active agent is suitable for treatingsaid disorder.
 55. The foamable composition of claim 9, comprising asolid, semi solid or waxy surfactant wherein the amount of surfactant orcombination of surfactants is between about 0.05% to about 10%.
 56. Thefoamable composition of claim 9, comprising a solid, semi solid or waxysurfactant which is soluble in oil and having a HLB or weighted averageHLB of less than about
 12. 57. A foamable waterless compositioncomprising: a. a therapeutically effective concentration of one or moreactive agents; b. a carrier delivery of the one or more active agentssuitable for stabilizing at least one of said one or more active agents,comprising i. about 25% to about 98% of at least polar solvent selectedfrom the group consisting of (1) a polyol; and (2) a polyethyleneglycol; ii. 0% to about 75% of a secondary polar solvent; iii. aneffective amount of an modulating agent iv. a stabilizing agent selectedfrom the group consisting of a surface-active agent; about 0.01% toabout 5% by weight of at least one polymeric agent and mixtures thereof.v. a liquefied or compressed gas propellant at a concentration of about3% to about 25% by weight of the total composition wherein the at leastone active agent is chemically unstable in the carrier in the absence ofa modulating agent; wherein the modulating agent comprises an effectiveamount of one or more agents that are capable of impeding saiddestabilization and or are capable of stabilizing the active agent bychelating a metal ion such that the modulating agent is capable ofreducing in the waterless carrier the availability of metal ions so thestability of at least one active agent is improved when compared to itsstability in the carrier without the modulating agent; wherein thecarrier is shakable or flowable; and wherein the composition is storedin an aerosol container and upon release expands to form a breakablefoam.
 58. The waterless composition of claim 57 further comprising oneor more agents that additionally are capable of impeding saiddestabilization and or are capable of stabilizing the active agentprimarily by modulating or adjusting the artificial pH of the carriersuch that the modulating agent is capable of producing in the waterlesscarrier an artificial pH or an artificial pH buffering effect at about apH or pH range in which the stability of at least one active agent isimproved when compared to its stability in the carrier without themodulating agent and or by impeding ionization and or by impedingoxidation.
 59. The waterless composition of claim 57, wherein themodulating agent is a chelating agent.
 60. The waterless composition ofclaim 57, wherein the chelating agent is sufficiently soluble orfunctional in the waterless solvent to enable it to “mop up” or “lock”metal ions.
 61. The waterless composition of claim 57, wherein thechelating agent is selected from the group consisting ofethylenediaminetetraacetic acid (“EDTA”) and salts thereof, disodiumEDTA, tetrasodium EDTA, calsium disodium EDTA;diethylenetriaminepentaacetic acid (“DTPA”) and salts thereof;hydroxyethlethylenediaminetriacetic acid (“HEDTA”) and salts thereof;and nitrilotriacetic acid (“NTA”) and salts thereof; acetyl trihexylcitrate, aminotrimethylene phosphonic acid, beta-alanine diacetic acid,bismuth citrate, calcium disodium edta, citric acid, cyclohexanediaminetetraacetic acid, diammonium citrate, dibutyl oxalate, diethyl oxalate,diisobutyl oxalate, diisopropyl oxalate, dilithium oxalate, dimethyloxalate, dipotassium edta, dipotassium oxalate, dipropyl oxalate,disodium edta, disodium edta-copper, disodium pyrophosphate, edta,etidronic acid, hedta, methyl cyclodextrin, oxalic acid, pentapotassium,triphosphate, pentasodium aminotrimethylene phosphonate, pentasodiumpentetate, pentasodium triphosphate, pentetic acid, phytic acid,potassium citrate, sodium citrate, sodium dihydroxyethylglycinate,sodium gluceptate, sodium gluconate, sodium hexametaphosphate, sodiummetaphosphate, sodium metasilicate, sodium oxalate, sodiumtrimetaphosphate, tea-edta, tetrahydroxypropyl ethylenediamine,tetrapotassium etidronate, tetrapotassium pyrophosphate, tetrasodiumedta, tetrasodium etidronate, tetrasodium pyrophosphate, tripotassiumedta, trisodium edta, trisodium hedta, trisodium nta, trisodiumphosphate, malic acid, fumaric acid, maltol, succimer, penicillamine,dimercaprol, and desferrioxamine mesilate.
 62. A foamable waterlesscarrier for use with a therapeutically effective concentration of one ormore active agents comprising i. about 25% to about 98% of at leastpolar solvent selected from the group consisting of (1) a polyol; and(2) a polyethylene glycol; 0% to about 75% of a secondary polar solvent;ii. an effective amount of a modulating agent iii. a stabilizing agentselected from the group consisting of a surface-active agent; about0.01% to about 5% by weight of at least one polymeric agent and mixturesthereof. iv. a liquefied or compressed gas propellant at a concentrationof about 3% to about 25% by weight of the total composition wherein atleast one active agent if present is susceptible, to one or more ofreaction, breakdown, ionization or oxidation; wherein the modulatingagent comprises an effective amount of one or more agents that arecapable of impeding said destabilization and or are capable ofstabilizing the active agent primarily by modulating or adjusting theartificial pH of the carrier such that the modulating agent is capableof producing in the waterless carrier an artificial pH or an artificialpH buffering effect at about a pH or pH range in which the stability ofat least one active agent is improved when compared to its stability inthe carrier without the modulating agent and or by chelating a metal ionsuch that the modulating agent is capable of reducing in the waterlesscarrier the availability of metal ions so the stability of at least oneactive agent is improved when compared to its stability in the carrierwithout the modulating agent; wherein the carrier is shakable orflowable; and wherein the composition is stored in an aerosol containerand upon release expands to form a breakable foam.